Fused pyrimidine derivative, process for preparation of same and pharmaceutical preparation comprising same as active ingredient

ABSTRACT

Disclosed is a fused pyrimidine of the formula [I] ##STR1## wherein R 1 , R 2 , and R 3  are as defined in the specification, Y represents a linking group of the formula ##STR2## wherein n is an integer of from 4 to 6, ##STR3## wherein A is a hydrogen atom or alkyl group; and Z represents a hydrogen atom, or other substituents; or Y and Z together represent an unsubstituted or substituted alkyl, alkenyl or arylalkyl group; or a 5- to 7-member heterocyclic ring which has a nitrogen atom, and further, an oxygen or sulfur atom as a hetero atom other than the nitrogen atom, being bonded via the nitrogen atom therein to the 4-position of the pyrimidine ring of the formula (I), a 5- to 7-member unsaturated heterocyclic ring which has 1 to 3 nitrogen atoms being bonded via the nitrogen atom therein to the 4-position of the pyrimidine ring of the formula (I), or a fused biheterocyclic ring constructed with 5- or 6-membered aromatic or non-aromatic rings, which has 1 to 3 nitrogen atoms in any position, being bonded via the nitrogen atom therein to the 4-position of the pyrimidine ring of the formula (I); and 
     m is an integer of from 1 to 3; 
     and a pharmaceutically acceptable acid addition salt thereof, as well as a process for producing same and a pharmaceutical preparation useful for a treatment of hypoxemia associated with respiratory diseases.

TECHNICAL FIELD

The present invention relates to a novel fused pyrimidine derivative, inparticular, a fused pyrimidine derivative having a substituted aminogroup at the 2- position of the pyrimidine ring and a substituted amino,oxy, thio, alkyl, alkenyl or arylalkyl group at the 4- position of thepyrimidine ring, and a pharmaceutically acceptable acid addition saltthereof. Further, the invention relates to a pharmaceutical preparationcomprising said derivative or said pharmaceutically acceptable acidaddition salt, as an active ingredient.

BACKGROUND ART

Among fused pyrimidine compounds,5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine derivatives having an aminogroup at their 2- and 4-positions and a process for producing thesecompounds are known in the art [see, Yamazaki et al., Synthesis, Vol. 3,266 (1983)]. Similarly, 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinederivatives having an amino group at their 2- and 4-positions are knownin the art [see, Ibid.; and I. Bitter et al., Heterocycles, Vol. 23,1167 (1985)]. Further, 5,6,7,8-tetrahydro-9H-pyrimido[4,5-b]azepinederivatives having an amino group at their 2- and 4-positions are alsoknown in the art [see, R. G. Glushkov et al., Khim. -Farm. Zh., Vol. 1,21 (1967)]. Nevertheless, biological activities of these fusedpyrimidines have not been known in the art.

Further, no fused pyrimidine derivatives having a substituted aminogroup at the 2-position of the pyrimidine ring and a substituted amino,oxy, thio, alkyl, alkenyl or arylalkyl group at its 4-position at thesame time, has been disclosed in the prior art, and it is not known thatthe same have a specific pharmacologic activity.

DISCLOSURE OF THE INVENTION

Our extensive and intensive researches on the fused pyrimidinederivatives resulted in a discovery of the compound defined as thegeneral formula [I] described below which have an excellentpharmacologic activity against hypoxemia associated with respiratorydiseases.

Note, the present inventors, in related research, found that somepyrrolo[2,3-d]pyrimidine derivatives have the same pharmacologicactivity as the compounds of the present invention, have filed a patentapplication, which is copending, prior to the filing of thisapplication.

Accordingly, in accordance with the present invention, novel fusedpyrimidine derivatives having the general formula [I] described below,and pharmaceutically acceptable acid addition salts thereof, and aprocess for preparation of the same and pharmaceutical preparationscomprising a compound selected from the same, are provided: ##STR4##wherein

R¹ represents a hydrogen atom, or an unsubstituted or substituted alkyl,alkenyl, arylalkyl, arylalkenyl or alkylcarbonyl group;

R² and R³, independently of each other, represent a hydrogen atom, or anunsubstituted or substituted alkyl, alkenyl, arylalkyl, arylalkenyl oralkylcarbonyl group;

or R² and R³ are optionally taken together with the adjacent nitrogenatom to form a saturated 5- to 7- membered ring, which may beconstructed with at least one hetero atom selected from N, O and S, withthe proviso that either R² or R³ represents a group other than ahydrogen atom;

Y represents a linking group of the formula ##STR5## wherein n is aninteger of from 4 to 6, ##STR6## wherein A is a hydrogen atom or alkylgroup; and

Z when bonded to a carbon atom on said linking group, represents ahydrogen atom, or carboxylic, amino or hydroxyl group, or anunsubstituted or substituted alkyl, aryl, arylalkyl, alkyloxy,alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, arylalkenylcarbonyloxy, alkylamino, alkenylamino,arylamino, arylalkylamino or alkylcarbonylamino group; and when bondedto an atom other than said carbon atom of the linking group andrepresents a hydrogen atom, or an unsubstituted or substituted alkyl,alkenyl, aryl, arylalkyl, arylalkenyl, alkylcarbonyl, arylalkylcarbonyl,arylalkenylcarbonly or arylcarbonyl group; or Y and Z together representan unsubstituted or substituted alkyl, alkenyl or arylalkyl group; or a5- to 7- member heterocyclic ring which has a nitrogen atom, andfurther, an oxygen or sulfur atom as a hetero atom other than thenitrogen atom, being bonded via the nitrogen atom therein to the4-position of the pyrimidine ring of the formula [I], a 5- to 7- memberunsaturated heterocyclic ring which has 1 to 3 nitrogen atoms, beingbonded via a nitrogen atom therein to the 4-position of the pyrimidinering of the general formula [I], or a fused biheterocyclic ring whichhas 1 to 3 nitrogen atoms in any position, being bonded via the nitrogenatom therein to the 4-position of the pyrimidine ring of the formula[I];

m is an integer of from 1 to 3; and

in said substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl,alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,alkylcarbonyloxy, alkyloxy-carbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, arylalkenylcarbonyloxy, alkylamino, arylamino,arylalkylamino and alkylcarbonylaminos groups, the substituentrepresents an alkyl, halogenated alkyl, alkyloxy, alkylcarbonyloxy,hydroxyl, amino, nitro or cyano group, or a halogen atom, which isbonded to chain or ring moiety in said substituted groups, or analkylene group taken together with a carbon atom in the chain moiety toform a ring.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention is disclosed in detail below.

An alkyl group or alkyl moiety of each group, unless defined otherwise,includes a C₁ -C₁₀ straight or branched chain aliphatic hydrocarbon,alicyclic hydrocarbon or cyclic-chain aliphatic hydrocarbon residue.Preferably, the alkyl group or the alkyl moiety includes a C₁ -C₆straight or branched alkyl group, a C₃ -C₇ cyclic alkyl group and a C₃-C₆ cyclic--C₁ -C₃ chain alkyl group. Specific examples of such groupare methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl,tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl andthe like.

The alkenyl group or alkenyl moiety of each group, unless otherwisedefined, includes a C₃ -C₆ straight or branched chain aliphatichydrocarbon, which has a double bond. Specific examples of such groupare 1-propenyl, allyl, 1-methylallyl, 2-methylallyl, 1-butenyl,2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 3-butenyl,2-pentenyl, 3-methyl-2-pentenyl, 2-hexenyl, 3-cyclopropylally,3-cyclopentenyl, 3-cyclohexyenyl, and the like.

The aryl group or aryl moiety of each group includes an aromatichydrocarbon cyclic or heterocyclic group constructed of 5- or 6-membered monocyclic or fused ring. Specific examples of such group arephenyl, 1-naphthyl, 2-naphthyl, 2-pyrrolyl, 2-furyl, 2-thienyl,2-pyridyl, etc., and in particular, phenyl, 1-naphthyl and 2-naphthyl,are preferred.

Accordingly, the arylalkyl group in accordance with the invention isintended to mean the alkyl group bonded to said aryl moiety, andpreferably a C₁ -C₆ straight or branched chain alky bonded to the arylmoiety. Specific examples of such groups are benzyl, 1-phenylethyl,1-methyl-1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, diphenylmethyl,triphenylmethyl, 1-naphthylmethyl, 1-(1-naphthy)ethyl,1,2,3,4-tetrahydronaphtharen-1-yl, 2-pyrrolylmethyl, 2-furfuryl,2-thienylmethyl, and the like.

The arylalkenyl group includes the alkenyl group bonded to said arylmoiety, and preferably a C₃ -C₆ alkenyl group bonded to said aromatichydrocarbone. Of these, in particular, the cinnamyl group, etc., ispreferred.

The alkylcarbonyl group includes the carbonyl group bonded to said alkylmoiety, and preferably a C₂ -C₇ alkylcarbonyl group. Specific examplesof such groups are acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl, hexanoyl,cyclopropylcarbonyl, and the like.

The arylcarbonyl group includes the carbonyl group bonded to said arylmoiety, such as benzoyl, toluoyl, naphthoyl, 2-pyrrolecarbonyl,2-furoyl, 2-thiophenecarbonyl, and the like.

The arylalkylcarbonyl group includes the carbonyl group bonded to saidarylalkyl moiety, such as phenyl acetyl, 3-phenylpropanoyl,4-phenylbutanoyl, diphenylacetyl, naphthylacetyl, 2-pyrrolylacetyl,2-furylacetyl, 2-thienylacetyl, and the like.

The arylalkenylcarbonyl group includes the carbonyl group bonded to saidarylalkenyl moiety, and particularly, cinnamoyl, etc. is preferred.

The alkylcarbonyloxy or arylcarbonyloxy group includes each oxygen atombonded to said alkylcarbonyl or arylcarbonyl moiety, respectively, suchas acetoxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy,pentanoyloxy, pivaloyloxy, hexanoyloxy, and the like; and benzoyloxy,toluoyloxy, naphthoyloxy, 2-pyrrolecarbonyloxy, 2-furoyloxy,2-thiophenecarbonyloxy, and the like.

Further, the arylalkyl- or arylalkenyl-carbonyloxy group includes eachoxygen atom bonded to said arylalkylcarbonyl or arylalkenylcarbonylmoiety, respectively, such as phenylacetoxy, 3-phenylpropanoyloxy,4-phenylbutanoyloxy, cinnamoyloxy, 2-pyrrolylacetoxy, 2-furylacetoxy,2-thienylacetoxy, and the like.

The alkyloxy group, which is constructed of said alkyl moiety and oxygroup, includes, for example, methoxy, ethoxy, propoxy, butoxy,isopropoxy, cyclopropylmethyloxy, and the like.

The alkyloxycarbony group includes a group in which a carbonyl group isbonded via an oxygen atom to said alkyl moiety, and is, for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbony, and the like.

The alkylamino group, alkenylamino group, arylamino group,arylalkylamino group and alkylcarbonylamino group are amino groups inwhich the hydrogen atom of the amino groups is substituted by said alkylgroup(s), alkenyl group(s), aryl group(s), arylalkyl group(s) andalkylcarbonyl groups(s), respectively, and includes, for example,methylamino, ethylamino, propylamino, allylamino, dimethylamino,diethylamino, anilino, benzylamino, 1-phenylethylamino,2-phenylethylamino, diphenylmethylamino, acetamide, propanamide, and thelike.

In the substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl,alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, arylalkenylcarbonyloxy, alkylamino, alkenylamino,arylamino, arylalkylamino and alkylcarbonylamino, the substituentrepresents a C₁ -C₄ alkyl, halogenated C₁ - C₄ alkyl, C₁ -C₄ alkyloxy,C₁ -C₅ alkylcarbonyloxy, hydroxyl, nitro, cyano or amino group, orhalogen atom, e.g., fluorine, chlorine, bromine or iodine atom, which isor are bonded to a chain or ring moiety; or an α, ω-alkylene group,which is taken together with a carbon atom in an alkyl chain moiety toform a ring, having e.g., ##STR7## as the substituted form.

According to the above-described definitions, the R¹ in the formula [I]represents a hydrogen atom or an unsubstituted or substituted alkyl,alkenyl, arylalkyl, arylalkenyl or alkylcarbonyl group. Suitablespecific examples of the alkyl group include methyl, ethyl, propyl,isopropyl, butyl, cyclopropyl, cyclopropylmethyl, trifluoromethyl,methoxymethyl, methoxyethoxymethyl, 2-aminoethyl, and the like. Suitablespecific examples of the alkenyl group include allyl, 2-methylallyl,2-butenyl, 3-methyl-2-butenyl, 2-fluoroallyl, 2-(trifluoromethyl)allyl,3-butenyl, and the like. Suitable specific examples of the arylalkylgroup include benzyl, 4-fluorobenzyl, 4-chlorobenzyl,3-(trifluoromethyl)benzyl, 4-methoxybenzyl, 2-phenylethyl,2-[(2-trifluoromethyl)phenyl]ethyl, triphenylemthyl,(4-methoxyphenyl)diphenylmethyl, 2-thienylmethyl, and the like. Suitablespecific examples of the allkenyl groups include cinnamyl, and the like.Suitable specific examples of the alkylcarbonyl group include acetyl,trifluoroacetyl, propanoyl, 2-methylpropanoyl, butanoyl, and the like.

The R² and R³ in formula [I] are identical with definitions of the R¹,respectively, and suitable examples thereof as well are identical withthose of R¹. The R² and R³ are optionally taken together with anadjacent nitrogen atom to form a saturated 5- to 7-membered ring, whichmay be constructed with at least one hetero atom (for example, N, O orS) in its ring other than the above-described nitrogen. Suitablespecific examples of the saturated 5- to 7- membered ring group include1-pyrrolidinyl, piperidino, 1-piperazinyl,4-[bis(4-fluorophenyl)methyl]-1-piperazinyl, morpholino, thiomorpholino,1-perhydro[1,4]diazepinyl, and the like.

The group having the formula --Y--Z in the formula [I] consists of alinking group which represents the formula: ##STR8## wherein n is aninteger of from 4 to 6, ##STR9## wherein A is a hydrogen atom or alkylgroup, --O-- or --S--, and a group as specifically disclosed below.

Of the groups having the formula ##STR10## wherein n is as definedabove, in particular, groups of the formula ##STR11## are preferred,suitable specific examples of the group Z include a hydrogen atom; analkyl group, such as methyl, propyl, cyclohexyl, and the like; an arylgroup, such as phenyl, 1-naphthyl, 2-naphthyl, 4-fluorophenyl, and thelike; an arylalkyl group, such as benzyl, 4-fluorobenzyl,4-metoxybenzyl, 4-nitrobenzyl, and the like; an alkylcarbonyloxy group,such as acetoxy, propanoyloxy, 2-methylpropanoyloxy, and the like; analkyloxy group, such as methoxy, ethoxy, propoxy, isopropoxy, and thelike; alkyloxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, and the like; an arylcarbonyloxygroup, such as benzoyloxy, naphthoyloxy, 2-furoyloxy,2-thiophenecarbonyloxy, and the like; an arylalkyl- orarylalkenylcarbonyloxy group, such as phenylacetoxy,4-nitrophenylacetoxy, 3-phenylpropanoyloxy, cinnamoyloxy, and the like;an alkyl-, alkenyl-, aryl-, arylalkyl- or alkylcarbonyl- amino group,such as methylamino, ethylamino, butylamino, allylamino,2-methylallylamino, anilino, benzylamino, bis(4-fluorophenyl)methylamino, acetamide, and the like; a carboxyl group, and a hydroxyl group.

In particular, in the groups of the formulae ##STR12## suitable specificexamples of Z include an unsubstituted or substituted alkyl group, suchas methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl,cyclopropylmethyl, cyclohexyl, trifluoromethyl, methoxymethyl,2-methoxyethyl, 2-hydroxyethyl, 2-aminoethyl, and the like; anunsubstituted or substituted alkenyl group, such as ally, 2-methylally,2-butenyl, 3-methyl-2-butenyl, 2-fluoroallyl, 2-(trifluoromethyl)allyl,3-butenyl, 3-cyclohexenyl, and the like; an unsubstituted or substitutedaryl group, such as phenyl, 1-naphthyl, 2-naphthyl, 2-pyrrolyl, 2-furyl,2-thienyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, andthe like; an unsubstituted or substituted arylalkyl or arylalkenylgroup, such as benzyl, 4-fluorobenzyl, 4-chlorobenzyl,3-(trifluoromethyl)benzyl, 4-methoxybenzyl, 4-cyanobenzyl,triphenylmethyl, (4-methoxyphenyl)diphenylmethyl,bis(4-fluorophenyl)methyl, diphenylmethyl, 1-phenylethyl,1-methyl-1-phenylethyl, 2-phenylethyl,2-[2-(trifluoromethyl)phenyl]ethyl, 2-(2-nitrophenyl)ethyl,2-(4-chlorophenyl)ethyl, 2-(4-methoxyphenyl)ethyl,2-(4-hydroxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl,2,2-(α,ω-butanediyl)-2-phenylethyl: ##STR13##fluorophenyl)-2,2-(α,ω-butanediyl)ethyl, 2,2-diphenylethyl,3-phenylpropyl, 1-(1-naphthyl)ethyl, 1,2,3,4-tetrahydronaphthalene-1-yl,2-pyrrolylmethyl, 2-furfuryl, 2-thienylmethyl, cinnamyl, and the like;an unsubstituted or substituted alkylcarbonyl group, such as acetyl,trifluoroacetyl, propanoyl, 2-methylpropanoyl, butanoyl, pivaloyl andthe like; an arylalkyl- or arylalkenyl-carbonyl group, such asphenylacetyl, 3-phenylpropanoyl, cinnamoyl, and the like; and anarylcarbonyl, such as benzoyl, naphthoyl, 2-furoyl, 2-thiophenecarbonyl,and the like, wherein said A is a hydrogen atom, methyl, ethyl orpropyl. Further, in particular, suitable specific examples of the Z asdescribed in the formula --O--Z and --S--Z, include an unsubstituted orsubstituted alkyl group, such as methyl, ethyl, propyl, isopropyl,butyl, cyclopropyl, cyclopropylmethyl, cyclohexyl, trifluoromethyl,methoxymethyl, 2-methoxyethyl, 2-hydroxyethyl, 2-aminoethyl, and thelike; an unsubstituted or substituted alkenyl, such as allyl,2-methylallyl, 2-butenyl, 3-methyl-2-butenyl, 2-fluoroallyl,2-(trifluoromethyl)allyl, 3-butenyl, and the like; an unsubstituted orsubstituted aryl group, such as phenyl, 1-naphthyl, 2-naphthyl,2-pyrrolyl, 2-furyl, 2-thienyl, 4-fluorophenyl, 4-chlorophenyl,4-trifluoromethylphenyl, and the like; and an unsubstituted orsubstituted arylalkyl or arylalkenyl, such as benzyl, 4-fluorobenzyl,4-chlorobenzyl, 3-(trifluoromethyl)-benzyl, 4-methoxybenzyl,triphenylmethyl, (4-methoxyphenyl)diphenylmethyl,1-methyl-l-phenylethyl, bis(4-fluorophenyl)methyl, diphenylmethyl,1-phenylethyl, 2-phenylethyl, 2-[2-(trifluoromethyl)phenyl]ethyl,2-(4-chlorophenyl)ethyl, 2-(4-methoxyphenyl)methyl,2-(4-fluorophenyl)ethyl, 2,2-(α,ω-butandiyl)-2-phenylethyl,[2-(4-fluorophenyl)-2,2-(α,ω-butandiyl)]ethyl, 2-pyrrolylmethyl,2-frufuryl, 2-thienylmethyl, cinnamyl, and the like.

Further, when Y and Z together are an unsubstituted or substitutedalkyl, alkenyl or arylalkyl group, or heterocyclic ring residue, whichare bonded via a nitrogen atom to the 4-position on the pyrimidine ringof the formula [I], these groups (or residues) include an unsubstitutedor substituted groups, such as ethyl propyl, butyl, hexyl, 1-propenyl,1-butenyl, 2-phenylethyl, 2-[2-(trifluoromethyl)phenyl]ethyl,2-(4-chlorophenyl)ethyl, 2-(4-methoxyphenyl)methyl,2-(4-fluorophenyl)ethyl, and the like, and a heterocyclic ring grouphaving the following formulae: ##STR14## Suitable specific examples offused pyrimidine derivative of the general formula [I] in accordancewith the present invention include the compounds containing thesubstituents described in the following table. Note, when the compoundhas asymmetric carbon atoms in the structure thereof, the compounds ofthe present invention include all optical isomers.

      ##STR15##      [I]      Compound No. R.sup.1 R.sup.2 R.sup.3 Y Z m         101 CH.sub.3 H      ##STR16##      ##STR17##      OAc 1      102 CH.sub.3 H     ##STR18##      NH      ##STR19##      1      103     ##STR20##      H      ##STR21##      ##STR22##      H 1      104     ##STR23##      H      ##STR24##      N(CH.sub.3) CH.sub.3 1      105 Ac H     ##STR25##      ##STR26##      F.sub.2 BH 1      106 H H CH.sub.3     ##STR27##      ##STR28##      2      107 H H CH.sub.3     ##STR29##      F.sub.2 BH 2      108 H H     ##STR30##      ##STR31##      F.sub.2 BH 2      109 H H     ##STR32##      ##STR33##      ##STR34##      2      110 H H     ##STR35##      ##STR36##      ##STR37##      2      111 H H     ##STR38##      NH      ##STR39##      2      112 H H     ##STR40##      ##STR41##      F.sub.2 BH 2      113 H H     ##STR42##      ##STR43##      H 2      114 H H     ##STR44##      NH      ##STR45##      2      115 H H     ##STR46##      ##STR47##      ##STR48##      2      116 H     ##STR49##      ##STR50##      NHAc 2      117 CH.sub.3 H CH.sub.3     ##STR51##      F.sub.2 BH 2      118 CH.sub.3 H     ##STR52##      ##STR53##      CO.sub.2 H 2      119 CH.sub.3 H     ##STR54##      ##STR55##      CO.sub.2 iPr 2      120 CH.sub.3 H     ##STR56##      ##STR57##      F.sub.2 BH 2      121 CH.sub.3 H     ##STR58##      NH      ##STR59##      2      122 CH.sub.3 H     ##STR60##      NH      ##STR61##      2      123 CH.sub.3 H     ##STR62##      S      ##STR63##      2      124 CH.sub.3 H     ##STR64##      NH      ##STR65##      2      125 CH.sub.3 H     ##STR66##      NH      ##STR67##      2      126 CH.sub.3 H     ##STR68##      ##STR69##      F.sub.2 BH 2      127 CH.sub.3 H     ##STR70##      NH      ##STR71##      2      128 CF.sub.3 H MMTr     ##STR72##      CH.sub.3 2      129 CH.sub.3 H Ac     ##STR73##      F.sub.2 BH 2      130     ##STR74##      H      ##STR75##      ##STR76##      F.sub.2 BH 2      131     ##STR77##      H Ac      ##STR78##      F.sub.2 BH 2      132     ##STR79##      H      ##STR80##      ##STR81##      CH.sub.3 2      133     ##STR82##      H      ##STR83##      ##STR84##      ##STR85##      2      134     ##STR86##      H      ##STR87##      ##STR88##      F.sub.2 BH 2      135     ##STR89##      H      ##STR90##      NH      ##STR91##      2      136     ##STR92##      H      ##STR93##      O      ##STR94##      2      137     ##STR95##      H      ##STR96##      S      ##STR97##      2      138     ##STR98##      H      ##STR99##      ##STR100##      2      139     ##STR101##      H      ##STR102##      ##STR103##      2      140     ##STR104##      H Ac      ##STR105##      F.sub.2      BH 2        141     ##STR106##      H      ##STR107##      ##STR108##      2      142     ##STR109##      H      ##STR110##      ##STR111##      2      143     ##STR112##      H      ##STR113##      ##STR114##      H 2      144     ##STR115##      H      ##STR116##      ##STR117##      ##STR118##      2      145     ##STR119##      H      ##STR120##      ##STR121##      H 2      146     ##STR122##      H      ##STR123##      ##STR124##      ##STR125##      2      147     ##STR126##      H      ##STR127##      ##STR128##      OH 2      148     ##STR129##      H      ##STR130##      ##STR131##      OAc 2      149     ##STR132##      H      ##STR133##      ##STR134##      ##STR135##      2      150     ##STR136##      H      ##STR137##      ##STR138##      ##STR139##      2      151     ##STR140##      H      ##STR141##      ##STR142##      NH.Ac 2      152     ##STR143##      H      ##STR144##      ##STR145##      ##STR146##      2      153     ##STR147##      H      ##STR148##      ##STR149##      H 2      154     ##STR150##      H      ##STR151##      ##STR152##      H 2      155     ##STR153##      H      ##STR154##      ##STR155##      CH.sub.3 2      156     ##STR156##      H      ##STR157##      ##STR158##      CH.sub.2 CH.sub.3 2      157     ##STR159##      H      ##STR160##      ##STR161##      ##STR162##      2      158     ##STR163##      H      ##STR164##      ##STR165##      ##STR166##      2      159     ##STR167##      H      ##STR168##      ##STR169##      F.sub.2 BH 2      160     ##STR170##      H      ##STR171##      ##STR172##      ##STR173##      2      161     ##STR174##      H      ##STR175##      ##STR176##      ##STR177##      2      162     ##STR178##      H      ##STR179##      ##STR180##      ##STR181##      2      163     ##STR182##      H      ##STR183##      ##STR184##      CH.sub.3 2      164     ##STR185##      H      ##STR186##      NH H 2      165     ##STR187##      H      ##STR188##      NH CH.sub.3 2      166     ##STR189##      H      ##STR190##      NH      ##STR191##      2      167     ##STR192##      H      ##STR193##      NH      ##STR194##      2      168     ##STR195##      H      ##STR196##      NH      ##STR197##      2      169     ##STR198##      H      ##STR199##      NH      ##STR200##      2      170     ##STR201##      H      ##STR202##      NH      ##STR203##      2      171     ##STR204##      H      ##STR205##      NH      ##STR206##      2      172     ##STR207##      H      ##STR208##      NH      ##STR209##      2      173     ##STR210##      H      ##STR211##      NH      ##STR212##      2      174     ##STR213##      H      ##STR214##      NH      ##STR215##      2      175     ##STR216##      H      ##STR217##      NH      ##STR218##      2      176     ##STR219##      H      ##STR220##      NH      ##STR221##      2      177     ##STR222##      H      ##STR223##      NH      ##STR224##      2      178     ##STR225##      H      ##STR226##      NH      ##STR227##      2      179     ##STR228##      H      ##STR229##      NH      ##STR230##      2      180     ##STR231##      H      ##STR232##      NH      ##STR233##      2      181     ##STR234##      H      ##STR235##      NH      ##STR236##      2      182     ##STR237##      H      ##STR238##      NH      ##STR239##      2      183     ##STR240##      H      ##STR241##      NH      ##STR242##      2      184     ##STR243##      H      ##STR244##      N(CH.sub.3) CH.sub.3 2      185     ##STR245##      H      ##STR246##      N(CH.sub.3) CH.sub.2 CH.sub.3 2      186     ##STR247##      H      ##STR248##      N(CH.sub.3)      ##STR249##      2      187     ##STR250##      H      ##STR251##      N(CH.sub.3)      ##STR252##      2      188     ##STR253##      H      ##STR254##      N(CH.sub.3)      ##STR255##      2      189     ##STR256##      H      ##STR257##      N(CH.sub.3)      ##STR258##      2      190     ##STR259##      H      ##STR260##      N(CH.sub.3)      ##STR261##      2      191     ##STR262##      H      ##STR263##      N(CH.sub.3)      ##STR264##       2      192     ##STR265##      H      ##STR266##      N(CH.sub.3)      ##STR267##      2      193     ##STR268##      H      ##STR269##      N(CH.sub.3)      ##STR270##      2      194     ##STR271##      H      ##STR272##      N(CH.sub.3)      ##STR273##      2      195     ##STR274##      H      ##STR275##      N(CH.sub.2      CH.sub.3)     ##STR276##      2      196     ##STR277##      H      ##STR278##      O CH.sub.3 2      197     ##STR279##      H      ##STR280##      O      ##STR281##      2      198     ##STR282##      H      ##STR283##      O      ##STR284##      2      199     ##STR285##      H      ##STR286##      S CH.sub.3 2      200     ##STR287##      H      ##STR288##      S      ##STR289##      2      201     ##STR290##      H      ##STR291##      S      ##STR292##      2      202     ##STR293##      H      ##STR294##      S      ##STR295##      2      203     ##STR296##      H      ##STR297##      S      ##STR298##      2      204     ##STR299##      H      ##STR300##      S      ##STR301##      2      205     ##STR302##      H      ##STR303##      S      ##STR304##      2            206     ##STR305##      H      ##STR306##      ##STR307##      2      207     ##STR308##      H      ##STR309##      ##STR310##      2      208     ##STR311##      H      ##STR312##      ##STR313##      2      209     ##STR314##      H      ##STR315##      ##STR316##      2      210     ##STR317##      H      ##STR318##      ##STR319##      2      211     ##STR320##      H      ##STR321##      ##STR322##      2      212     ##STR323##      H      ##STR324##      ##STR325##      2      213     ##STR326##      H      ##STR327##      ##STR328##      2      214     ##STR329##      H      ##STR330##      ##STR331##      2      215     ##STR332##      H      ##STR333##      ##STR334##      2      216     ##STR335##      H Ac      ##STR336##      F.sub.2 BH 2      217     ##STR337##      CH.sub.3      ##STR338##      ##STR339##      F.sub.2 BH 2      218     ##STR340##      ##STR341##      ##STR342##      ##STR343##      F.sub.2      BH 2       219     ##STR344##      ##STR345##      ##STR346##      ##STR347##      2        220      ##STR348##      H      ##STR349##      ##STR350##      NHCH.sub.2 CH.sub.3 2      221     ##STR351##      H      ##STR352##      ##STR353##      OAc 2      222     ##STR354##      H      ##STR355##      ##STR356##      Ac 2      223     ##STR357##      H      ##STR358##      ##STR359##      F.sub.2 BH 2      224     ##STR360##      H      ##STR361##      ##STR362##      F.sub.2 BH 2      225     ##STR363##      H      ##STR364##      NH      ##STR365##      2      226     ##STR366##      H      ##STR367##      NH      ##STR368##      2      227     ##STR369##      H      ##STR370##      NH      ##STR371##      2      228     ##STR372##      H      ##STR373##      ##STR374##      CH.sub.3 2      229     ##STR375##      H      ##STR376##      NH      ##STR377##      2      230     ##STR378##      H      ##STR379##      ##STR380##      F.sub.2 BH 2      231     ##STR381##      H      ##STR382##      ##STR383##      OCH.sub.2 CH.sub.3 2      232     ##STR384##      H      ##STR385##      ##STR386##      CH.sub.3 2      233     ##STR387##      H      ##STR388##       NH      ##STR389##      2      234     ##STR390##      H      ##STR391##      ##STR392##      F.sub.2 BH 2      235     ##STR393##      H Ac      ##STR394##      F.sub.2 BH 2      236     ##STR395##      H      ##STR396##      NH      ##STR397##      2      237     ##STR398##      H      ##STR399##      NH      ##STR400##      2      238     ##STR401##      H      ##STR402##      ##STR403##      H 2      239     ##STR404##      H      ##STR405##      ##STR406##      ##STR407##      2      240     ##STR408##      H      ##STR409##      NH      ##STR410##      2      241     ##STR411##      H      ##STR412##      NH      ##STR413##      2      242     ##STR414##      H      ##STR415##      NH      ##STR416##      2      243     ##STR417##      H      ##STR418##      N(CH.sub.3)      ##STR419##      2      244 Ac H Ac     ##STR420##      F.sub.2 BH 2      245 CH.sub.3 H     ##STR421##      ##STR422##      F.sub.2 BH 3      246     ##STR423##      H      ##STR424##      ##STR425##      OAc 3      247     ##STR426##      H      ##STR427##      NH      ##STR428##      3      248 Ac CH.sub.3 Ac     ##STR429##      Ac 3

wherein F₂ BH, MMTr, Ac and iPr represent ##STR430## respectively.

The fused pryimidine derivatives in accordance with the presentinvention may be acid addition salts, and suitable examples of acidsforming such salts include inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, boricacid, carbonic acid, and the like; organic carboxylic acids such asformic acid, acetic acid, propionic acid, citric acid, succinic acid,maleic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, andthe like; and organic sulfonic acids such as methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,camphorsulfonic acid, and the like.

According to the present invention, a fused pyrimidine derivative andpharmaceutically acceptable acid addition salt thereof can be preparedby condensation of halogenated fused pyrimidine derivative representedby the general formula [II] ##STR431## wherein R¹, R², R³, R⁴ and m arethe same meaning as defined above and X is halogen, with a compoundrepresented by the general formula [III]

    Z--Y--H                                                    [III]

wherein Y and Z are the same meanings as defined above, followed byaddition with an inorganic or organic acid, if necessary.

The compound of the formula [II] may be a novel or known compound. Thepreparation of the latter is disclosed in the art [see, R. G. Glushkovet. al., Khim. -Farm. Zh., Vol. 1, 21 (1967)]. The novel compound can bealso prepared according to the reference example as described below andthe above literature. Examples of the halogen atom in the halogenatedfused pyrimidine derivative include a chlorine, bromine and iodine atom.Such atoms are highly reactive, and thus a desired fused pyrimidinederivative having the formula [I] can be produced by reacting such atomswith a compound represented by the formula [III].

The compound of the formula [III] adequates to this reaction may beavailable or prepared by a known method per se.

The compounds of the formula [III] are amines, alcohols or thiolscorresponding to the groups as defined for the formula Z--Y--X.Especially the compounds corresponding to the previously listed suitableexamples for the formula Z--Y-- are preferable in use.

The above-described reaction can be conducted, for example, by reactingone equivalent of a halogenated fused pyrimidine derivative representedby the formula [II] with 1 to 30 equivalents of an amine, alcohol orthiol represented by the formula [III] in the absence or presence of asolvent under atomospheric pressure or into an autoclave. If necessary,the addition of a base, and examples of the base include inorganic basessuch as sodium hydroxide, potassium hydroxide, sodium carbonate andpotassium carbonate, and organic bases such as triethylamine,diethylaniline, dimethylaniline and pyridine.

Further, the presence of an additive may be allowed, and the additivesinclude iodides such as potassium iodide, sodium iodide, lithium iodide,tetrabutylammonium iodide, and the like, or fluorides such as potassiumfluoride, sodium fluoride, cesium fluoride, tetrabutylammonium fluoride,and the like.

The reaction temperature is in the range of -20° to 300° C., preferablyin the range of room temperature to 200° C., and the reaction iscompleted in 72 hours.

Preferable reaction solvents include halogenated hydrocarbons such asdichloromethane, chloroform, trichloromethane and carbon tetrachloride,aromatic hydrocarbons such as benzene, toluene and xylene, alcohols suchas methanol, ethanol, isopropyl alcohol, butanol and tert-butanol,ethers such as diethyl ether, tetrahydrofuran and dioxane, and aproticpolar solvents such as dimethylformamide, dimethylacetamide,dimethylsulfoxide and sulfolane, etc.

After the completion of the reaction, the reaction mixture can besubjected to ordinary separation and purification procedures, that is,concentration, solvent extraction, recrystallization, chromatography,etc., to isolate a desired fused pyrimidine derivative represented bythe formula [I]. The compound [I] can be converted to a pharmaceuticallyacceptable acid addition salt according to a conventional method.

Also almost all the compounds of the formula [II] is novel. Newlydeveloped synthetic routes to [I] via [II] are shown in the followingscheme: ##STR432## wherein,

R¹, R² and R³, and X, Y and Z have the same definitions as those of theformulae [II] and [III], and TBDMSOTf representstert-butyldimethylsilyltrifluoromethanesulfonate.

The reaction steps up to the compound of the formula [II] aresummarized, as follows:

The 3-ethoxycarbonyl alicyclic amide (1) be treated withmethyl-trifluoromethanesulfonate to give an iminoether, which can beannulated with guandine in a strong alkaline condition to give thecompound of the formula (2).

The resulting compound (2) can be halogenated by a general method (e.g.,using phosphorus oxychloride) to give the compound of formula (3).

The compounds of the formula [I] that have a group--Y--Z via a carbonatom thereof bonded to the pyrimidine ring, are novel, and therefore amethod for preparation of the same has been unknown.

Newly developed synthetic routes are shown in the following scheme:##STR433## wherein

R¹, R², and R³, and X have the same definitions as those of the formula[II], and TBDMSOTf and Et representtert-butyldimethysilyl-trifluoromethanesulfonate and an ethyl group,respectively.

The crosscoupling reaction of a compound (3) and an alkynyl metalcompound, preferably diethyl-alkynylaluminum, can be performed in thepresence of tetrakis(triphenylphosphine)palladium to afford a compound(5). Hydrogenation of (5) gives compounds (6) and (7).

Alternatively, the compounds of the formula [I] can be obtained by usinga tert-butyl dimethylsilyl group as a protective group, and repeatingthe above to selectively introduce the substituents R¹, R² and R³.

The present compounds exhibit an excellent pharmacological actionagainst hypoxemia associated with various respiratory diseases.

It is generally known that, in pneumonopathy, e.g., pneumonectasis,bronchitis, bronchial asthma, interstitial pneumonia andpneumonophthisis, the partial pressure of oxygen (PaO₂) in arterialblood is lowered as the pathosis becomes more severe or chronic. In thiscase, symptoms such as a feeling of fatigue, shortness of breath andchoking occur, and in a serious state, dyspnea, cyanosis and adisturbance of consciousness occur.

Therefore, a pharmaceutical preparation capable of raising and improvingthe PaO₂ lowered due to such respiratory diseases has been desired inthe art. Further, it is often shown that, in such diseases, the partialpressure of carbon dioxide (PaCO₂) in arterial blood increasesconversely to a decrease of PaO₂, and in this case, there is a need fora pharmaceutical preparation that cannot only increases PaO₂ but alsodecreases PaCO₂.

The compounds in the present invention have actions such that theyenhance the respiratory function of the lung, that one mainly increasesonly PaO₂, and that another increases PaO₂ and decreases PaCO₂, at thesame time, and thus the present compounds are useful for the treatmentof various respiratory diseases.

The pharmacological effect of the compound in accordance with thepresent invention can be demonstrated by an acute hypoxemia model usingan experimental animal. For example, the acute hypoxemia (having a lowerPaO₂ value) model can be prepared by administering intratracheally afine powder, such as carbon powder, silica gel, glass beads or dentalimpression material, in a small animal, e.g., rat, to lower therespiratory function [see, for example, Munakata et al., Preprints ofthe 35th Symposium of Japanese Society of Anesthesiology, 179 (1988)].Also, acute hypoxemia (having a lower PaO₂ value) model can be preparedby administering intratracheally a mucosa-prophlogistic acid, e.g.,acetic acid and crotonic acid.

Therefore, the compounds in the present invention were orally orparenterally administered to the above-described model animal, and thearterial blood was collected after a given period of time and subjectedto a measurement of PaO₂ (or PaCO₂) by a blood gas analyzer. As aresult, a significant increase of PaO₂ (or decrease of PaCO₂) incomparison with that before the administration, was observed.

The fused pyrimidine derivative and its acid addition salt in accordancewith the present invention can be administered orally or as a parenteraladministration such as an intravenous, subcutaneous, intramuscular,percutaneous, intrarectal or other administration.

Examples of the dosage form for the oral administration include tablets,pills, granules, powders, suspensions and capsules.

The tablets can be formulated by a conventional method through the useof, for example, excipients such as lactose, starch and crystallinecellulose; binders such as carboxymethylcellulose, methylcellulose andpolyvinylpyrrolidone; and disintegrators such as sodium alginate, sodiumhydrogencarbonate and sodium laurylsulfate.

Similarly, the pills, powders and granules can be formulated by aconventional method through the use of the above-described excipients,etc. The solutions and suspensions can be formulated by a conventionalmethod through the use of, for example, glycerin esters such astricaprylin and triacetin and alcohols such as ethanol. The capsules canbe formulated by filling a granule, a powder or a solution into acapsule made of gelatin, and the like.

Examples of the dosage form for a subcutaneous, intramuscular andintravenous administration include injections in the form of an aqueousor nonaqueous solution. In the aqueous solution, use is made of, forexample, a physiological saline, and the like. In the nonaqueoussolution, use is made of, for example, propylene glycol, polyethyleneglycol, olive oil, ethyl oleate, and the like. If necessary,preservatives, stabilizers, etc., may be added thereto. The injectionscan be sterilized by a proper treatment, such as a filtration throughthe bacterial filter, or by an addition of a bacteriocide.

Examples of the dosage forms for a percutaneous administration includeointments and creams. The ointments and creams can be formulated by aconventional method through the use of fatty oils, such as castor oiland olive oil, petrolatums, etc., in the case of the ointments, andemulsifiers, such as diethylene glycol and sorbitan monofatty acidesters, etc., in the case of the creams.

Conventional suppositories, such as gelatin soft capsules, may be usedfor a rectal administration.

Although the dosage of the bicyclic pyrimidine derivative of the presentinvention varies depending upon the kind of disease, administrationpath, age and sex of patient, and severity of disease, etc., it isusually 1 to 500 mg/day/adult.

All of the compounds provided by the present invention (testingsubstances) have more than 2 g/kg (rat, P.O.) of LD₅₀.

EXAMPLES

The present invention will now be described in more detail withreference to the following Examples.

Reference Example: Synthesis of8-allyl-2-alylamino-4-chloro-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidineProcedure A

A solution of 14 g (75.8 mmol) of2-amino-4-chloro5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine and 12 ml (87mmol) of triethylamine in 240 ml of dichloromethane was cooled to 0° C.,and 25.3 g (79 mmol) of p-anisylchlorodiphenylmethane was added thereto.The mixture was stirred at that temperature for one hour. The reactionmixture was poured into water and extracted twice with 200 ml ofdichloromethane. The organic phase was dried over magnesium sulfate,filtered, and the solvent was evaporated to remove from the filtrate. Toa solution of 36.2 g of the resultant crude product in 150 ml of DMF wasadded. 15.3 ml (167 mmol) of allyl iodide, the mixture was cooled to 0°C., and treated with 10 g (250 mmol) of sodium hydride (oleaginous,60%). It was stirred at that temperature for 2 hours. The reactionmixture was gradually dropwise poured onto iced water, acidified with 80ml of 5N hydrochloric acid, heated at 70° C. and stirred for 2 hours.The byproduct and decomposed material were extracted twice with 200 mlof an ether/hexane (=1/1) solution from the reaction mixture. The waterlayer was neutralized with 5N sodium hydroxide and the product wasextracted with ethyl acetate. The organic layer was dried over magnesiumsulfate and filtered, and the solvent was evaporated to be removed fromthe filtrate. Recrystallization from hexane-isopropyl ether yield 6.71 g(33%) of the desired8-allyl-2-allylamino-4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine.

Procedure B

To a solution of 69 g (370 nmol) of2-amino-4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine in anhydrousdichloromethan (450 ml) was added 70 ml (500 mmol) of triethylamine, andthen cooled to -37° C. Then, under inert gas atmosphere, to the reactionmixture was dropwise added 102 ml (450 mmol) of tertbutyldimethylsilyltrifluoromethanesulfonate over a period of 30 minutes, and the mixturewas stirred at that temperature for 1.5 hours. The suspension turned toa red-colored solution. The reaction solution was poured into 300 ml ofwater. After usual work up, the product was extracted with 300 ml ofdichloromethane. The combined dichloromethane layer was dried overpotassium carbonate, and then the solvent was evaporated from thefiltrate. To the resulting oily residue was added 300 ml of hexane, thenheated to 80° C. with stirring. An insoluble oily residue then removedby decantation. The target compound was extracted with 200 ml of hexanefrom the oily residue. The combined hexane layer was evaporated to give112 g (370 mmol) of2-tert-butyldimethylsilylamino-4-chloro-5,6,7,8tetrahydropyrido[2,3-d]pyrimidinein the form of white crystals. (Yield 99%)

Physical Properties

¹ H-NMR(CDCl₃)σ:

0.23 (6H, s), 0.93 (9H, s), 1.89 (2H, tt, J=6 and 6 Hz), 2.61 (2H, t,J=6 Hz), 3.33 (2H, dt, J=2.5 and 6 Hz), 4.3 (1H, br), 5.0 (1H, br)

125 g (420 mmol) of2-tert-butyldimethylamino-4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinethus obtained and 87 ml (1.00 mol) of allylbromide were dissolved in 630ml of anhydrous DMF, and the solution was cooled to 0° C. Then, underinert gas atmosphere, to the solution was slowly added a suspension of60% sodium hydride 42 g (1.00 mol) in DMF (150 ml), followed by afurther stirring for one hour at room temperature. After the reactionwas completed, it was treated with 1 l of cooled water, and extractedwith hexane (500 ml ×2). The combined organic layer was dried oversodium sulfate, and concentrated to yield oily residue. Then, to itresidue was added 150 ml of 12N hydrochloric acid and 200 ml of water,followed by stirring for 15 minutes. The impurities were extracted withhexane (250 ml ×2). To the water layer was added ammonia water until theformation of the precipitation was completed. The resulting precipitateswere filtered off, washed with water, dried, and 95 g of crude productsthus obtained were recrystallized from 400 ml of ethanol to yield 83 g(315 mmol) of the title compound. (Yield 75%)

Physical Properties:

¹ H-NMR(CDCl₃)σ:

1.87 (2H, tt, J=5.5 and 6 Hz), 2.63 (2H, t, J=6 Hz), 3.28 (2H, t, J=5.5Hz), 3.96 (2H, t, J=5.5 Hz), 4.8 (1H, br), 5.0-5.2 (4H, m), 5.5-6.1 (2H,m)

UV (EtOH) λmax, nm 300, 223

m.p. 107.5°-108.0° C.

Example 1: Synthesis of8-allyl-2-allylamino-4-(4-methyl-l-piperazinyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine

A mixture of 43 g (160 mmol) of8-allyl-2-allylamino-4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidineprepared in Reference Example A or B, 22 g (170 mmol) of lithium iodide,and 300 ml of N-methylpiperazine in an autoclave was stirred at 160° C.for 15 hours. After the reaction was completed, the reaction solutionwas washed with 1 l of water, and extracted with ethylacetate (500 ml×4). The resulting organic layer was washed with water (500 ml ×3),dried over sodium sulfate, filtered, and then concentrated to give 50 gof oily residue. The resulting oily residue was recrystallized from 500ml of hexane to yield 40 g of8-allyl-2-allylamino-4-(4-methyl-l-piperazinyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine.(prisms; mp. 81° C.) To the mixture was added 170 ml of acetonitrile,dissolved at 70° C., and then cooled to -15° C., followed byrecrystallization to yield 37.8 g (yield 69%) of a free base. (needles;mp. 80.5°-81.5° C.). Then, 70.0 g of the free base derived from the sameprocedure was ground in a mortar, dissolved in 600 ml of diethylether.To the solution was added saturated hydrogen chloride ether solutionwith stirring until precipitation was completed. The precipitate wasfiltered and thoroughly washed with diethylether to yield 84.6 g of thehydrochloride in the form of white crystals. The crude crystals wererecrystallized from 550 ml of isoprapanol to yield 74 g of8-allyl-2-allylamino-4-(4-methyl-1-piperazinyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinehydrochloride. (yield of the hydrochloride 87%)

Physical Properties of Free Base:

¹ H-NMR(CDCl₃)σ:

1.7-1.9 (2H,m), 2.37 (3H, s), 2.47 (2H, t, J=6 Hz), 2.58 (4H, t, J=4.5Hz), 3.29 (2H, t, J=5.5 Hz), 3.36 (4H , t, J=4.5 Hz), 3.96 (2H, t, J=5Hz), 4.20 (2H, d, J=6 Hz), 4.5 (1H, br), 5.0-5.3 (4H, m), 5.6-6.1 (2H,m)

Physical Properties of Hydrochloride:

UV (EtOH) λmax, nm 224, 302

Elemental Analysis: for C₁₈ H₃₁ N₆ Cl₂

Calculated: C. 53.86: H. 7.54: N. 20.93: C₁.17.66

Found: C. 53.79: H. 7.46: N. 20.81: C₁.17.56

Example 2: Synthesis of2-N,N-diallylamino-4-(2-Phenylethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine

Under argon atmosphere, to a solution (380 μl, 3.5 mmol) ofphenylacetylene in anhydrous tetrahydrofuran (THF) was added a 1.58Msolution (2.0 ml, 3.3 mmol) of butyllithium in hexane at 0° C. andstirred at the same temperature for 15 minutes, and to the reactionmixture was further added a 1M solution (3.3 ml, 3.3 mmol) ofdiethylaluminium chloride in hexane, and stirred at room temperature for15 minutes. Then, to the reaction solution was added tetrakis(triphenylphospine) palladium (120 mg, 0.1 mmol) and2-amino-4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (185 mg, 1mmol), which was stirred at reflux temperature for 7 hours. The reactionsolution was treated with an aqueous sodium hydroxide solution andextracted with ethylacetate. Then, the organic layer was dried, andconcentrated. The resulting residue was purified with alumina columnchromatography (mobile phase: ethylacetate/hexane=2/1) to yield 63 mg(0.25 mmol, 25%) of 2-amino-4-phenylethynyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidineo

Physical Properties

¹ H-NMR(CDCl₃)σ:

1.95 (2H, m), 2.80 (2H, t, J=6 Hz), 3.3-3.5 (2H, m), 4.7 (2H, br), 5.5(1H, br), 7.2-7.6 (5H, m)

IR (KBr) 1570, 1600, 2200, 3100, 3250 cm⁻¹

To a solution of the resulting2-amino-4-phenylethynyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-(1.9g, 7.5 mmol) in 15 ml ethanol-acetic acid (8:1) was added 300 mgplatinum oxide. The mixture was stirred in an atmosphere of hydrogen atroom temperature for 4 hours. After the reaction was completed, thesolution was filtered, the filtrate was neutralized, and extracted withdichloromethane, and the organic layer was dried and concentrated toyield a residue. The residue was purified with ODS partitionchromatography (mobile phase: methanol) to yield 1.2 g of a mixturecontaining2-amino-4-(2-phenylethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine as amain component.

Physical Properties:

¹ H-NMR(CDCl₃)σ:

1.8-2.0 (2H, m), 2.3-2.9 (4H, m), 2.6 (2H, t, J=6 Hz), 3.2-3.4 (2H m),4.7 (2H, br), 5.3 (1H, br), 7.2-7.3 (5H, m)

A solution of the resulting2-amino-4-(2-phenylethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (120mg, 0.54 mmol) and allyliodide (440 μl, 4.8 mmol) in 1.5 ml of anhydrousDMF was cooled to 0° C., sodium hydride (60%, 210 mg, 5.4 mmol) wasadded under nitrogen or argon atmosphere, and the mixture was stirred atroom temperature for 3 hours. After the reaction was completed, thereaction solution was washed with water, extracted, dried andconcentrated. The resulting residue was purified with silica-gel columnchromatography (mobile phase: ethylacetate/hexane=1/1 to 2/1) to yield40 mg (0.11 mmol) (yield 20%) of2-N,N-diallylamino-4-(2-phenylethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine.

Physical Properties:

¹ H-NMR(CDCl₃)σ:

1.7-1.9 (2H, m), 2.44 (2H, t, J=6 Hz) 2.6-2.8 (2H, m), 2.9-3.1 (2H, m)3.21 (2H, t, J=5.5 Hz), 4.09 (6H, d, J=5.5 Hz), 5.0-5.2 (6H, m), 5.6-6.1(3H, m), 7.21 (5H, s)

In the following Examples, the compounds in accordance with the presentinvention were prepared by the procedures described in Example 1 or 2,using corresponding starting materials and reactants, respectively, aswell as reaction solvents, coexisting bases and additives indicated inthe following tables, and each reaction was performed under theconditions, i.e., reaction temperature, reaction time, and reactionvessel, indicated in the following tables.

    __________________________________________________________________________    (*A: Autoclave B: Atmospheric pressure)                                                                                     UV of acid  Reaction                                             Yield                                                                             Type of salt                                                                           addition                                                                            Reaction                                                                            temp.                                                of  M.P. of acid                                                                           salt  solvent                                                                             Reaction               Com-                          free                                                                              addition salt                                                                          EtOH  Coexisting                                                                          time                Ex.                                                                              pound                                                                             .sup.1 H-NMR data of free base                                                                          base                                                                              Recrystallization                                                                      λ.sub.max                                                                    base  Reaction            No.                                                                              No. (CDCl.sub.3) δ(ppm) (%) solvent  (nm)  Additive                                                                            vessel              __________________________________________________________________________     3 104 3.06(6H, s), 2.8-3.45(4H, m), 3.8-4.1(4H, m), 4.5(1H,                                                   28  HCl.salt --    DMF   160° C.             br), 4.9-5.3(4H, m), 5.4-6.2(2H, m)                                                                         102° C. --    44 h                                                     EtOH/Et.sub.2 O                                                                              LiI   A                    4 107 1.7-1.9(2H, br), 2.3-2.5(6H, m, br), 2.85(3H, d, J                                                      72Hz),                                                                            --       --    --    170° C.             3.2(6H, t-like), 4.25(1H, s), 4.4(1H, br), 4.8(1H,                                                                         --),  20 h                       6.96(4H, t, J=9Hz), 7.25-7.45(4H, m)         LiI   B                    5 108 1.7- 1.8(2H, m, br), 2.4(2H, t-like), 2.41(4H, t-like),                                                 65  HCl.salt 206   DMF   170° C.             3.2(6H, br), 3.94(2H, t, J=5.5Hz), 4.24(1H, s),                                                                      245   --    16 h                       4.5(1H, t, J=5.5Hz), 4.8(1H, br), 5.0(1H, dd, J=9&2Hz),                                                              306         B                          5.18(1H, dd, J=14&2Hz), 5.7-6.1(1H, m), 6.96(4H, t,                           J=9Hz), 7.25-7.45(4H, m)                                                6 112 1.7-1.9(2H, br), 1.73(3H, s), 2.4(2H, br), 2.41(4H,                                                     55),                                                                              HCl.salt 206   --    170° C.             3.26(4H, br), 3.3(2H, br), 3.87(2H, d, J=6Hz), 4.24(1H,                                                              245   --    20 h                       s), 4.6(1H, t, J=6Hz), 4.77(1H, br), 4.8(1H, br),                                                                    3065  LiI   B                          (1H, br), 6.96(4H, t, J=9Hz), 7.2-7.4(4H, m)                            7 117 1.6-1.9(2H, br), 2.3-2.5(6H, m), 2.89(3H, d, J=5Hz),                                                    75  HCl.salt --    --    170° C.             3.08(3H, s), 3.19(4H, t, J=5Hz), 3.20(2H, t, J=5Hz),                                                                       --    15 h                       4.24(1H, s), 4.5(1H, br), 6.95(4H, t, J=8.5Hz),                                                                            LiI   B                          7.25-7.43(4H, m)                                                        8 120 1.6-1.9(2H, br), 2.40(2H, t-like), 2.42(4H, t-like),                                                    58  HCl.salt --    --    170° C.             3.06(3H, s), 3.18(4H, t-like), 3.20(2H, br),                                                                152˜156° C.                                                                     --    20 h                       3.97(2H, t, J=5.5Hz), 4.24(1H, s), 4.5(1H, t, br,                                                           --             LiI   B                          J=6Hz), 5.05 (1H, dd, J=8&1Hz), 5.2(1H, dd,                                   J=15&1Hz), 5.7-6.2(1H, m), 6.96(4H, t, J=9Hz),                                7.25-7.43(4H, m)                                                        9 121 1.7-2.1(2H, m), 2.29(2H, t-like, J=6.4Hz), 3.03(3H,                                                     100 HCl.salt 298   --    170° C.             3.21(2H, dd, J=3.7Hz, 5.5Hz), 3.8-4.2(5H, m), 4.5(1H,                                                       123˜125° C.                                                               234   --    15 h                       br), 4.9-5.4(4H, m), 5.8-6.2(2H, m)                                                                         acetone        LiI   A                   10 129 1.6-1.9(2H, m, br), 2.4-2.5(6H, m, br), 2.54(3H,                                                        25, --       --    DMF   120° C.             3.07(3H, s), 3.21(4H, t, J=5Hz), 3.31(2H, t-like),                                                                         --    10 h                       4.25(1H, s), 6.97(4H, t, J=9Hz), 7.25-7.45(4H, m)                                                                          --    B                   11 130 0.87(3H, t, J=7Hz), 1.5-1.9(4H, m), 2.41(2H, t,                                                         75  HCl.salt 205   --    170° C.             J=5.5Hz), 2.42(4H, br), 3.16(4H, t, J=5Hz), 3.25(2H,                                                        159˜164° C.                                                               220   --    20 h                       m), 3.46(2H, t, J=7Hz), 3.95(2H, t, J=5.5Hz), 4.24                                                                   308   LiI   B                          (1H, s), 4.5(1H, t-like), 5.05(1H, dd, J=9&2Hz),                              5.7-6.2(1H, m), 5.2(1H, dd, J=15&2Hz), 6.96(4H, t,                            J=9Hz), 7.25-7.43(4H, m)                                               12 131 0.87(3H, t, J=7.5Hz), 1.55(2H, m), 1.8(2H, m, br),                                                      30  --       --    DMF   120° C.             2.4(6H, t-like, br), 2.54(3H, s), 3.21(4H, t, J=5Hz),                                                                      --    15 h                       3.31(2H, t, J=5Hz), 3.45(2H, t, J=7.5Hz), 4.25(1H,                                                                         --,   B                          6.96(4H, t, J=9Hz), 7.25-7.45(4H, m)                                   13 134 0.2-0.5(4H, m), 0.9(1H, m), 1.7-1.9(2H, m),                                                             65  HCl.salt --    --    170° C.             2.40(2H, t, J=5Hz), 2.42(4H, t, J=5Hz), 3.17(4H,                                                            133˜135° C.                                                                     --    20 h                       J=5Hz), 3.36(2H, t, J=5Hz), 3.44(2H, d, J=7Hz),                                                             --             LiI   B                          3.95(2H, t, J= 5.5Hz), 4.24(1H, s), 4.5(1H, t, J=6Hz),                        5.05(1H, dd, J=9&2Hz), 5.2(1H, dd, J=14&2Hz),                                 6.96(4H, t, J=9Hz), 7.25-7.45(4H, m)                                   14 140 0.2-0.5(4H, m), 0.8-1.3(1H, m), 1.7-1.9(2H, br),                                                        20  --       --    DMF   120° C.             2.4-2.5(6H, br), 2.54(3H, s), 3.21(4H, t, J=5Hz),                                                                          --    10 h                       3.39(2H, t, J=5Hz), 3.42(2H, d, J=7Hz), 4.25(1H,                                                                           --,   B                          6.97(4H, t, J=9Hz), 7.25-7.45(4H, m)                                   15 143 1.81(4H, m), 1.7-1.9(2H, m), 2.59(2H, t, J=5.5Hz),                                                      87  HCl.salt 207   --    140° C.             3.20(2H, t, J=5.5Hz), 3.48(4H, t, J=6.5Hz),                                                                 95˜98° C.                                                                 241   --    15 h                       3.94(2H, t, J=5.5Hz), 4.18(2H, d, J=5.5Hz), 4.5(1H,                                                         iPr.sub.2 O-iPrOH                                                                      307   LiI   A                          5.0-5.3(4H, m), 5.6-6.2(2H, m)                                         16 145 1.59(2H, br), 1.61(4H, br), 1.7-1.9(2H, m),                                                             80  HCl.salt 218   --    150° C.             2.48(2H, t, J=6Hz), 3.10(4H, t-like, br),                                                                   94˜95° C.                                                                 240   --    15 h                       3.25(2H, t, J=5.5Hz), 3.96(2H, t, J=6Hz), 4.18(2H,                                                          iPr.sub.2 O-iPrOH                                                                      308   LiI   A                          J=6Hz), 4.50(1H, br), 5.0-5.3(4H, m), 5.6-6.2(2H, m)                   17 146 1.7-2.0(6H, m, br), 2.5(2H, t, J=6Hz), 2.6-3.0(4H,                                                      83, fumarate 213   --    150° C.             3.3(2H, t, J=5.5Hz), 3.6(1H, br), 3.8(1H, br),                                                              154.5˜159.5° C.                                                           300   --    30 h                       4.0(2H, t, J=6Hz), 4.2(2H, d, J=6Hz), 4.5(1H, br),                                                          EtOH           LiI   A                          5.0-5.3(4H, m), 5.6-6.1(2H, m), 7.3(5H, s)                             18 147 1.5-2.1(6H, m, br), 2.47(2H, t, J=5Hz), 2.6(1H, br),                                                    47  --       --    --    130° C.             2.7-3.0(2H, m), 3.25(2H, t, J=5Hz), 3.4-3.7(3H, m),                                                                        --    20 h                       3.94(2H, t, J=5.5Hz), 4.17(2H, d, J=5.5Hz), 4.7(1H,                                                                        LiI,  B                          5.0-5.3(4H, m), 5.6-6.1(2H, m)                                         19 148 1.6-1.9(6H, m, br), 2.05(3H, s), 2.47(2H, t, J=5.5Hz),                                                  25  fumarate 218   DMF   120° C.             2.8-3.4(4H, m, br), 3.29(2H, t, J=5Hz), 3.5(1H, t-like),                                                    144˜147° C.                                                               298   --    10 h                       3.96(2H, t, J=5.5Hz), 4.18(2H, d, J=5.5Hz), 4.5(1H,                                                         EtOH           --    B                          5.0-5.3(4H, m), 5.6-6.1(2H, m)                                         20 153 1.5-1.9(9H, m, br), 1.8-2.0(2H, m, br), 2.51(2H, t,                                                     756Hz),                                                                           HCl.salt 215   --    150° C.             3.21(2H, t, J=6Hz), 3.45(4H, t, J=5.5Hz),                                                                            243   --    15 h                       3.95(2H, t, J=5.5Hz), 4.18(2H, d, J=5.5Hz), 4.4(1H,                                                                  310,  LiI   A                          5.0-5.3(4H, m), 5.6-6.1(2H, m)                                         21 154 1.7-2.0(2H, m), 2.48(2H, t, J=6Hz), 2.9-3.0(4H, m),                                                     85  fumarate --    --    140° C.             3.0-3.1(4H, m), 3.26(2H, t, J=5.5Hz), 3.96(2H, t,                                                                          --    15 h                       J=5.5Hz), 4.18(2H, d, J=5.5Hz), 4.6(1H, br), LiI   A                          5.0-5.3(4H, m), 5.6-6.1(2H, m)                                         22 156 1.10(3H, t, J=7.3Hz), 1.6-1.9(2H, m), 2.3-2.6(8H,                                                       100 HCl.salt 302   --    160° C.             3.1-3.3(6H, m), 3.95(2H, t-like, J=5.5Hz),                                                                  200˜210° C.                                                               223   --    15 h                       4.18(2H, d-like, J=5.5Hz), 4.55(1H, br-t, J= 5.5Hz),                                                        i-PrOH-        LiI   A                          4.9-5.3(4H, m), 5.6-6.2(2H, m)                                                                              i-Pr.sub.2 O                             23 157 1.7-1.9(2H, m), 2.52(2H, t, J=6Hz), 3.0-3.4(10H,                                                        65, HCl.salt 206   --    160° C.             3.97(2H, t, J=5.5Hz), 4.19(2H, d, J=5.5Hz),                                                                 168˜170° C.                                                               243   --    15 h                       4.6(1H, br), 5.0-5.3(4H, m), 5.6-6.1(2H, m),                                                                         307   LiI   B                          6.8-7.1(4H, m)                                                         24 158 1.7-1.9(2H, m), 2.4-2.6(6H, m), 3.19(4H, t, J=5Hz),                                                     70  HCl.salt 211   --    160° C.             3.24(2H, t, J=5Hz), 3.49(2H, s), 3.95(2H, t, J=5.5Hz),                                                               242   --    15 h                       4.18(2H, t, J=5.5Hz), 4.6(1H, br), 5.0-5.3(4H, m),                                                                   307   LiI   B                          5.6-6.1(2H, m), 6.98(2H, t, J=9Hz), 7.2-7.3(2H, m)                     25 159 1.7-1.9(2H, m), 2.4(6H, m, br), 3.18(4H, t, J=5Hz),                                                     40  HCl.salt 205   --    140° C.             3.23(2H, t, J=5.5Hz), 3.95(2H, t, J=5.5Hz),                                                                 131˜133° C.                                                               243   --    12 h                       4.17(2H, d, J=6Hz), 4.24(1H, s), 4.5(1H, t, J=5.5Hz),                                                       iPrOH    309   LiI   A                          5.0-5.3(4H, m), 5.7-6.1(2H, m), 6.96(2H, t, J=9Hz),                           7.3-7.45(4H, m)                                                        26 163 1.5-2.15(4H, m), 2.36(3H, s), 2.3-2.75(6H, m),                                                          96  HCl.salt 307   --    160° C.             3.1-3.3(2H, m), 3.4-3.6(4H, m), 3.94(2H, t-like,                                                            140˜142° C.                                                               223   --    15 h                       J=5.5Hz), 4.18(2H, d-like, J=5.5Hz), 4.5(2H, br-t,                                                          i-PrOH-        LiI   A                          J=5.5Hz), 4.95-5.35(4H, m), 5.6-6.2(2H, m)                                                                  i-Pr.sub.2 O                             27 164 1.7-2.1(2H, m), 2.35(2H, t-like, J=6.4Hz),                                                              68  HCl.salt 292   H.sub.2 O                                                                           195° C.             3.23(2H, t-like, J=6.1Hz), 3.8-4.6(7H, m), 4.9-5.3(4H,                                                      183˜188° C.                                                               238   --     7 h                       5.5-6.2(2H, m)                EtOH-          --    A                                                        Et.sub.2 O                               28 165 1.7(1H, br),1.7-1.9(2H, m), 2.27(2H, t, J=6Hz),                                                         41  fumarate 210   CH.sub.3                                                                            160° C.             2.95(3H, d, J=5Hz), 3.19(2H, t, J=5.5Hz),                                                                   155˜158° C.                                                                     NHCHO 50 h                       3.99(2H, t, J=5.5Hz), 4.16(2H, d, J=5.5Hz), 4.5(1H,                                                         EtOH     291   K.sub.2 CO.sub.                                                                     A                          5.0-5.3(4H, m), 5.7-6.1(2H, m)               --                        29 166 1.7(1H, br), 1.7-1.9(2H, m), 2.29(2H, t, J=6Hz),                                                        59  fumarate 211   --    180° C.             3.19(2H, t, J=5.5Hz), 3.36(3H, s),3.50-3.65(4H, m),                                                         151.5˜152.5° C.                                                                 --    15 h                       3.96(2H, t, J=5.5Hz), 4.16(2H, d, J=5.5Hz), 4.4(1H,                                                         EtOH     291   LiI   A                          5.0-5.3(4H, m), 5.7-6.1(2H, m)                                         30 168 1.6(1H, br), 1.7-1.9(2H, m), 2.29(2H, t, J=6Hz),                                                        53  fumarate 212   --    180° C.             3.19(2H, t, J=5.5Hz), 3.96(2H, t-like, J=5.5Hz),                                                              149˜150.5° C.                                                                 --    15 h                       4.03(2H, t, J=5.5Hz), 4.16(2H, d, J=5.5Hz),                                                                 EtOH     291   LiI   A                          4.5(1H, br), 5.0-5.3(6H, m), 5.7-6.1(3H, m)                            31 169 1.75-2.15(2H, m), 2.43(2H, t-like, J=6.5Hz),                                                            30  fumarate --    --    190° C.             3.25(2H, t-like, J=5Hz), 3.85-4.05(2H, m), 4.1-4.3(2H,                                                      147˜150° C.                                                                     --     5 h                       4.6-4.9(1H, br), 4.95-5.35(4H, m), 5.6-6.2(3H, m),                                                          EtOH           LiI   B                          6.9-7.6(5H, m)                                                         32 170 1.8-2.05(2H, m), 2.1-2.4(2H, m), 3.20(2H, t-like,                                                       655.3Hz),                                                                         HCl.salt 299   --    160° C.             3.97(2H, t-like, J=5.3Hz), 4.1-4.7(6H, m), 4.9-5.3(4H,                                                      142˜143° C.                                                               237   --    14 h                       5.6-6.2(2H, m), 7.2-7.5(5H, m)                                                                              i-PrOH   208   LiI   B                   33 171 1.7-1.9(2H, m), 2.14(2H, t, J=6Hz), 2.86(2H, t, J=7Hz),                                                 81  fumarate 210   --    150° C.             3.17(2H, t, J=5.5Hz), 3.65(2H, q, J=6.5Hz),                                                                 154˜158° C.                                                                     --    40 h                       4.00(2H, t, J=5.5Hz), 4.15(2H, d, J=5.5Hz), 4.5(1H,                                                         EtOH     289   LiI   A                          5.0-5.3(4H, m), 5.7-6.1(2H, m)                                         34 172 1.8-2.2(4H, m), 2.84(2H, t, J=7.0Hz),                                                                   68  fumarate 288   --    170° C.             3.18(2H, t-like, J=5.3Hz), 3.6(2H, q-like, J=6.4Hz),                                                        105˜109° C.                                                                     --    17 h                       3.8-4.2(5H, m), 4.5(1H, br), 4.9-5.3(4H, m),                                                                EtOH     225   LiI   B                          5.55-6.2(2H, m), 7.0-7.3(4H, m)                                        35 173 1.7-2.3(4H, m), 2.80(2H, t, J=6.4Hz),                                                                   59  fumarate 287   --    170° C.             3.17(2H, t-like, J=5.5Hz), 3.7(2H, q-like, J=6.1Hz),                                                        91˜93° C.                                                                 226   --     6 h                       3.79(3H, s), 3.7-4.2(5H, m), 4.5(1H, br-t), 4.9-5.3(4H,                                                     EtOH           LiI   B                          5.6-6.2(2H, m), 6.88(2H, d, J=9.3Hz), 7.12(2H, d, J=9.3Hz)             36 175 2.16(2H, t, J=6Hz), 2.67(2H, t, J=7.5Hz),                                                               97  fumarate 292   --    140° C.             3.15(2H, t, J=5.5Hz), 3.42(2H, dt, J=7&6Hz),                                                                141˜144° C.                                                                     --    20 h                       3.94(2H, t, J=5.5Hz), 4.13(2H, d, J=5.5Hz),                                                                 EtOH     215   LiI   A                          4.5(1H, br, t-like), 5.0-5.3(4H, m), 5.6-6.1(2H, m),                          7.19(5H, s)                                                            37 176 1.6-2.2(12H, m), 3.12(2H, t-like, J=6.2Hz),                                                             60  --             --    180° C.             3.5-3.8(3H, m), 3.97(2H, t-like, J=5.9Hz),                                                                  --       --    --     5 h                       4.18(2H, d-like, J=5.9Hz), 4.45(1H, br-t, J=5.5Hz),                                                         --             LiI   B                          4.95-5.3(4H, m), 5.6-6.2(2H, m), 7.2-7.4(5H, m)                        38 177 1.6-2.3(10H, m), 3.13(2H, t-like, J=4.2Hz), 3.5-3.8(3H,                                                 81, fumarate 289   --    180° C.             3.97(2H, t-like, J=6Hz), 4.13(2H, d-like, J=6Hz),                                                           136˜140° C.                                                               213   --     4 h                       4.5(1H, br-t, J=6Hz), 5.0-5.4(4H, m), 5.6-6.2(2H,                                                           EtOH           LiI   B                          6.9-7.4(4H, m)                                                         39 178 1.6-2.1(4H, m), 3.12(2H, t-like, J=4.3Hz),                                                              47  fumarate 290   --    180° C.             3.8-4.6(8H, m), 4.9-5.3(4H, m), 5.6-6.2(2H, m),                                                             110˜120° C.                                                               213   --     8 h                       7.1-7.4(10H, m)               EtOH           LiI   B                   40 183 1.6-2.2(2H, m), 2.50(2H, t, J=6.4Hz),                                                                   13  fumarate 311   DMF   150° C.             3.31(2H, t-like, J=3.5Hz), 3.90(2H, t-like, J=4.1Hz),                                                       119˜120° C.                                                               221   --    20 h                       4.20(2H, d-like, J=5.7Hz), 4.6-5.3(6H, m),                                                                  EtOH           --    B                          5.6-6.1(2H, m), 7.2-7.6(3H, m), 7.7-8.0(2H, m)                         41 184 1.7-1.9(2H, m), 2.53(2H, t, J=6Hz), 2.83(6H, s),                                                        63  HCl.salt 214   DMF   150° C.             3.25(2H, t, J=5.5Hz), 3.97(2H, t, J=5.5Hz),                                                                 127˜129° C.                                                               243   K.sub.2 CO.sub.3                                                                    40 h                       4.19(2H, d, J=5.5Hz), 4.5(1H, br), 5.0-5.3(4H, m),                                                          iPr.sub.2 O                                                                            307   --    A                          5.6-6.1(2H, m)                                                         42 185 1.13(3H, t, J=7Hz), 1.7-1.9(2H, m), 2.50(2H, t, J=6Hz),                                                 65  HCl.salt --    --    150° C.             2.80(3H, s), 3.18(2H, t, J=7Hz), 3.22(2H, t, J=5.5Hz),                                                      103˜105° C.                                                                     --    30 h                       3.96(2H, t, J=5.5Hz), 4.19(2H, d, J=5.5Hz), 4.5(1H,                                                         iPr.sub.2 O-iPrOH                                                                            LiI   A                          5.0-5.3(4H, m), 5.6-6.1(2H, m)                                         43 186 1.6(1H, br), 1.7-1.9(2H, m), 2.54(2H, t, J=6Hz),                                                        61  HCl.salt 217   --    160° C.             2.93(3H, s), 3.26(2H, t, J=5.5Hz), 3.47(2H, t-like,                                                           73-73.5° C.                                                                   242   --    15 h                       3.7-3.9(2H, m), 3.92(2H, t, J=5.5Hz), 4.18(2H, d,                                                           iPr.sub.2 O-CH.sub.3 CO.sub.3                                                          307   LiI   A                          J=5.5Hz), 4.6(1H, br), 5.0-5.3(4H, m),                                        5.6-6.1(2H, m)                                                         44 187 0.91(3H, t, J=6.5Hz), 1.0-1.7(4H, m), 1.7-1.9(2H,                                                       63, HCl.salt 217   --    150° C.             2.50(2H, t, J= 6Hz), 2.81(3H, s), 3.22(2H, t, J=6.5Hz),                                                       74˜76.5° C.                                                             241   --    80 h                       3.24(2H, t, J=5.5Hz), 3.96(2H, t, J=5.5Hz),                                                                 iPrOH    307   LiI   A                          4.19(2H, d, J=5.5Hz), 4.5(1H, br), 5.0-5.3(4H, m),                            5.6-6.1(2H, m)                                                         45 189 1.7-1.9(2H, m), 2.56(2H, t, J=6Hz), 2.75(3H, s),                                                        40  fumarate 213   --    150° C.             3.25(2H, t, J=5.5Hz), 3.96(2H, t, J=5.5Hz),                                                                   102˜102.5° C.                                                                 --    30 h                       4.20(2H, d, J=5.5Hz), 4.42(2H, s), 4.5(1H, br),                                                             EtOH     298   LiI   A                          5.0-5.4(4H, m), 6-6.1(2H, m), 7.30(5H, s-like)                         46 192 1.6-1.9(2H, m), 2.46(2H, t-like, J=5.3Hz), 2.7-3.0(2H,                                                  25, --       --    --    180° C.             2.86(3H, s), 3.1-3.5(4H, m), 3.97(2H, t, J=5.5Hz),                                                          --             --     3 h                       4.18(2H, d-like, J=5.5Hz), 4.5(1H, br-t, J=5.5Hz),                                                          --             LiI   B                          4.9-5.3(4H, m), 5.6-6.2(2H, m), 6.1-7.3(5H, m)                         47 196 1.7-1.9(2H, m), 2.47(2H, t, J=6Hz), 3.22(2H, t, J=5.5Hz),                                               99  HCl.salt 208   MeOH  110° C.             3.82(3H, s), 3.97(2H, t, J=5.5Hz), 4.16(2H, d, J=5.5Hz),                                                      93˜93.5° C.                                                                   NaOMe 15 h                       4.6(1H, br), 5.0-5.3(4H, m), 5.6-6.1(2H, m)                                                                 iPr.sub.2 O-iPrOH                                                                      305   --    A                   48 197 1.7-1.9(2H, m), 2.51(2H, t, J=6Hz), 3.22(2H, t, J=5.5Hz),                                               75  HCl.salt 206   DMF   130° C.             3.96(2H, t, J=5.5Hz), 4.16(2H, d, J=5.5Hz), 4.5(1H,                                                                        NaH,  15 h                       4.76(2H, t, J=5.5Hz), 5.0-5.4(6H, m), 5.6-6.7(3H,                                                                    304   --    B                   49 198 1.7-1.9(2H, m), 2.53(2H, t, J=6Hz), 3.23(2H, t, J=5.5Hz),                                               74  fumarate 216   DMF   120° C.             3.97(2H, t, J=5.5Hz), 4.17(2H, d, J=5.5Hz), 4.6(1H,                                                         119˜122° C.                                                                     NaH   13 h                       5.0-5.3(4H, m), 5.31(2H, s), 5.6-6.1(2H, m),                                                                EtOH     284   --    A                          7.3-7.4(5H, br)                                                        50 199 1.8-2.0(2H, m), 2.47(3H, s), 2.5(2H, t, J=6Hz),                                                         80  HCl.salt 225   DMF   100° C.             3.24(2H, t, J=5.5Hz), 3.99(2H, t, J=5.5Hz),                                                                 118˜122° C.                                                                     NaSMe 15 h                       4.16(2H, d, J=5.5Hz), 4.5(1H, br), 5.0-5.3(4H, m),                                                          iPr.sub.2 O-iPrOH                                                                      309   --    B                          5.6-6.1(2H, m)                                                         51 200 1.2-2.2(13H, m, br), 2.46(2H, t, J=6Hz),                                                                95  fumarate 123   DMF    90° C.             3.22(2H, t, J=5.5Hz), 3.7-3.9(1H, br),                                                                      154˜157° C.                                                                     NaH    2 h                       3.97(2H, t, J=5.5Hz), 4.15(2H, d, J=5.5Hz), 4.5(1H,                                                         EtOH     307   --    B                          5.0-5.3(4H, m), 5.6-6.1(2H, m)                                         52 202 1.7-1.9(2H, m), 2.59(2H, t, J=6Hz), 3.27(2H, t, J=5.5Hz),                                               73  fumarate 219   DMF   100° C.             3.75(2H, t, J=5.5Hz), 4.16(2H, d, J=5.5Hz), 4.5(1H,                                                           153˜155.5° C.                                                                 NaH    4 h                       5.0-5.3(4H, m), 5.6-6.0(2H, m), 7.2-7.5(4H, m)                                                              EtOH     312   --    B                   53 203 1.72(3H, d, J=7Hz), 1.7-1.95(2H, m),                                                                    100 fumarate --    DMF    90° C.             2.43(2H, t-like, J=6.5Hz), 3.21(2H, t-like, J=5.5Hz),                                                       113˜115° C.                                                                     NaH    1 h                       3.85-4.25(4H, m), 4.5-4.8(1H, br), 4.95-5.35(5H,                                                            EtOH           --    B                          5.55-6.2(2H, m), 7.15-7.5(5H, m)                                       54 204 1.7-1.9(2H, m), 2.48(2H, t, J=6Hz), 2.98(2H, t, J=8Hz),                                                 82  fumarate 217   DMF   100° C.             3.24(2H, t, J=5.5Hz), 3.35(2H, t, J=8Hz),                                                                   141˜144° C.                                                                     NaH    3 h                       4.02(2H, t, J=5.5Hz), 4.17(2H, d, J=5.5Hz), 4.6(1H,                                                         EtOH     307   --    B                          5.0-5.3(4H, m), 5.7-6.1(2H, m), 7.1-7.3(5H, m)                         55 205 1.7-2.0(2H, m), 1.8-2.1(2H, m), 2.48(2H, t, J=6Hz),                                                     91  fumarate 213   DMF   100° C.             2.74(2H, t, J=8Hz), 3.13(2H, t, J=7Hz),                                                                     111.5˜   NaH   3 H                        3.23(2H, t, J=5.5Hz), 3.95(2H, t, J=5.5Hz),                                                                 112.5° C.                                4.15(2H, d, J=5.5Hz), 4.5(1H, br), 5.0-5.3(4H, m),                                                          EtOH     306   --    B                          5.6-6.1(2H, m), 7.2(5H, s)                                             56 209 1.7-1.9(2H, m), 2.47(2H, t, J=6Hz), 3.16(4H, t, J=4.5Hz),                                               95  HCl.salt 219   --    150° C.             3.26(2H, t, J=5.5Hz), 3.76(4H, t, J=4.5Hz),                                                                 103˜106° C.                                                               241   --    15 h                       3.95(2H, t, J=5.5Hz), 4.18(2H, d, J=5.5Hz),                                                                 iPr.sub.2 O-iPrOH                                                                      307   LiI   A                          4.6(1H, br), 5.0-5.3(4H, m), 5.6-6.1(2H, m)                            57 210 1.7-1.9(2H, m), 2.45(2H, t, J=6Hz), 2.69(4H, t-like,                                                    50  fumarate 217   --    160° C.             J=5Hz), 3.26(2H, t, J=5.5Hz), 3.46(4H, t-like, J=5Hz),                                                      154.5˜155° C.                                                                   --    20 h                       3.95(2H, t, J=5.5Hz), 4.18(2H, d, J=5.5Hz), 4.6(1H,                                                         EtOH     298   LiI   A                          5.0-5.3(4H, m), 5.6-6.1(2H, m)                                         58 211 1.7-1.9(2H, m), 2.62(2H, t, J=6Hz), 3.36(2H, t, J=5.5Hz),                                               85  HCl.salt --    --    140° C.             3.99(2H, t, J=5.5Hz), 4.22(2H, d, J=5.5Hz),  --    15 h                       4.5(1H, br), 5.0-5.3(4H, m), 5.6-6.1(2H, m), --    B                          7.11(1H, t, J=1Hz), 7.32(1H, m), 7.91(1H, s-like)                      59 212 1.6-2.0(4H, m), 2.30(2H, t, J=6Hz), 3.20(2H, t, J=5.5Hz),                                               40  fumarate 212   --    100° C.             3.34(2H, t-like), 3.50(2H, t-like), 3.97(2H, t, J=5.5Hz),                                                                  --     6 h                       4.15(2H, d, J=5.5Hz), 4.3(1H, br), 4.5(1H, br),                                                             EtOH     290   --    B                          5.0-5.3(4H, m), 5.6-6.1(2H, m)                                         60 213 1.7-1.9(2H, m), 2.15-2.25(2H, m), 2.51(2H, t, J=6Hz),                                                   99  HCl.salt 218   --    150° C.             3.26(4H, t, J=5.5Hz), 3.73(2H, br), 3.96(2H, t, J=5.5Hz),                                                   102˜104° C.                                                               242   --    80 h                       4.19(2H, d, J=5.5Hz), 4.5(1H, br), 5.0-5.3(4H, m),                                                          Et.sub.2 O                                                                             308   LiI   A                          5.6-6.1(4H, m)                                                         61 214 1.7-1.9(2H, m), 2.57(2H, t, J=6Hz), 2.96(2H, t, J=6Hz),                                                 93  fumarate 215   --    150° C.             3.28(2H, t, J=5.5Hz), 3.45(2H, t, J=6Hz),                                                                   119˜125° C.                                                                     --    15 h                       3.98(2H, t, J=5.5Hz), 4.19(2H, d, J=5.5Hz), 4.40(2H,                                                        EtOH     299         A                          4.6(1H, br), 5.0-5.3(4H, m), 5.6-6.1(2H, m), 7.12(4H, s)               62 215 1.7-1.9(2H, m), 2.84(2H, t, J=6Hz), 3.40(2H, t, J=5.5Hz),                                               41  HCl.salt 225   DMF   150° C.             4.04(2H, t, J=5.5Hz), 4.29(2H, d, J=5.5Hz), 4.9(1H,                                                                  255,  NaH   30 h                       5.0-5.3(4H, m), 5.7-6.1(2H, m), 7.3-7.6(2H, m),                                                                      288   LiI   B                          8.0-8.15(2H, m)                                                        63 216 1.7-1.9(2H, m), 2.3-2.5(6H, m, br), 2.52(3H, s),                                                        25  --       --    DMF   110° C.             3.22(4H, t, J=5Hz), 3.29(2H, t, J=5.5Hz),    --    30 h                       4.13(2H, d, J=5.5Hz), 4.25(1H, s), 5.0-5.2(2H, m),                                                                         LiI   B                          5.7-6.1(1H, m), 6.97(4H, t, J=9Hz), 7.25-7.45(4H, m)                   64 217 1.7-1.9(2H, m), 2.4(6H, br), 3.00(3H, s), 3.2(6H,                                                       60),               --    160° C.             4.1-4.25(5H, m), 5.0-5.2(4H, m), 5.6-6.1(2H, m),                                                                           --    20 h                       6.95(4H, t, J=9Hz), 7.25-7.45(4H, m)         LiI   B                   65 218 1.7-1.9(2H, m), 2.47(6H, t, J=5Hz), 3.18(4H, t, J=5Hz),                                                 65  --       --    --    160° C.             3.24(2H, t, J=5.5Hz), 4.11(4H, d, J=5.5Hz),  --    20 h                       4.16(2H, d, J=5.5Hz), 4.23(1H, s), 5.0-5.2(6H, m),                                                                         LiI   B                          5.6-6.1(3H, m), 6.96(4H, t, J=9Hz), 7.25-7.45(4H, s)                   66 223 1.66(3H, s), 1.7-1.9(2H, m), 2.43(6H, t-like, J=5.5Hz),                                                 65  HCl.salt 205   --    130° C.             3.19(4H, t, J=5Hz), 3.24(2H, br), 3.94(2H, t, J=5.5Hz),                                                     145˜170° C.                                                               243   --    15 h                       4.16(2H, s), 4.24(1H, s), 4.6(1H, br), 4.8(2H, br),                                                         (dec.)                                          5.03(1H, dd, J=2&15Hz), 5.12(1H, dd, J=2&15Hz),                                                             iPr.sub.2 O                                                                            309   LiI   A                          6.95(4H, t, J=9Hz), 7.25-7.45(4H, m)                                   67 224 1.65(3H, s), 1.74(3H, s), 1.7-1.9(2H, m),                                                               55  HCl.salt 205   --    140° C.             2.43(6H, t-like, J=5.5Hz), 3.18(6H, t-like, J=5Hz),                                                         124˜128° C.                                                               243   --    20 h                       3.89(2H, d, J=5.5Hz), 4.15(2H, s), 4.24(1H, s),                                                             iPr.sub.2 O                                                                            310   LiI                              4.6(1H, br), 4.7-4.9(4H, m, br), 6.95(4H, t, J=9Hz),                          7.2-7.45(4H, m)                                                        68 230 1.7-1.9(2H, br), 2.43(6H, t-like, J=5.5Hz),                                                             60  HCl.salt 206   --    170° C.             3.18(4H, t, J=5Hz), 3.25(2H, br), 3.94(2H, t, J=5.5Hz),                                                     154˜157° C.                                                               245   --    20 h                       4.25(1H, s), 4.6(1H, br), 4.81(2H, s), 5.0-5.2(2H,                                                          iPr.sub.2 O                                                                            310   LiI   B                          5.7-6.1(1H, m), 6.96(4H, t, J=9Hz), 7.2-7.4(4H, m),                           7.25(5H, s)                                                            69 233 1.7-2.0(2H, m), 2.30(2H, t-like, J=5.7Hz),                                                              43  HCl.salt 292   --    140° C.             3.15(2H, t-like, J=5.2Hz), 3.8-4.2(5H, m), 4.4(1H,                                                          130˜137° C.                                                                     --    20 h                       4.80(2H, s), 4.85-5.4(4H, m), 5.7-6.2(2H, m), 7.25(5H,                                                      EtOH     215   LiI   B                   70 234 1.7-1.9(2H, br), 2.43(6H, t-like, J=5.5Hz),                                                             65  --       --    --    170° C.             3.19(4H, t, J=5Hz), 3.24(2H, t, J=5.5Hz), 4.25(1H,                                                                         --,   20 h                       4.6(1H, t-like, br), 4.50(2H, d, J=6Hz), 4.78(2H,                                                                          LiI   B                          6.96(4H, t, J=9Hz), 7.2-7.45(14H, m)                                   71 235 1.7-1.9(2H, br), 2.4(6H, t-like, J=5.5Hz), 2.46(3H,                                                     30, --       --    --    140° C.             3.1-3.4(6H, br), 4.25(1H, s), 4.77(2H, s),   --    10 h                       6.96(4H, t, J=9Hz), 7.24(5H, s), 7.25-7.45(4H, m)                                                                          LiI   B                   72 240 1.7-2.1(2H, m), 2.2-2.5(2H, m), 2.87(2H, dd, J=8&6Hz),                                                  30  fumarate --    --    170° C.             3.1-3.35(2H, m), 3.73(2H, dd, J=8&6Hz), 3.9-4.3(6H,                                                         190˜197° C.                                                                     --    22 h                       4.95-5.4(4H, m), 5.7-6.3(2H, m), 7.23(5H, s)                                                                EtOH           LiI   A                   73 242 1.8-2.1(2H, m), 2.30(2H, t-like, J=6.8Hz),                                                              20  --       --    --    170° C.             3.24(2H, t-like, J=4.4Hz), 3.9-4.7(8H, m), 5.0-5.4(4H,                                                                     --,   14 h                       5.8-6.6(4H, m), 7.2-7.5(5H, m)                                                                              --       --    LiI   A                   74 244 1.7-1.9(2H, br), 2.35-2.55(6H, br), 2.48(3H, s),                                                        15  --       --    DMF   120° C.             2.53(3H, s), 3.38(4H, t, J=5Hz), 3.77(2H, t, J=5.5Hz),                                                                     --    10 h                       4.25(1H, s), 6.98(4H, t, J=9Hz), 7.2-7.45(4H, m)                                                                           --    B                   __________________________________________________________________________

Example 75: Effect on Partial Pressure Value of Gases in Arterial Blood(Intravenous Injection System) Method A

Male Wistar strain rats (body weight about 300 g) were anesthetizedintra-peritonealy with urethane, and a cannula was inserted into therespiratory tract and the femoral artery, respectively. A suspension(30-100 μm, 10 mg/ml) of carbon powder in a corn oil was intratrachealyinjected to induce a hypoxemia state (PaO₂ : 50-60 mmHg). A compound inthe present invention was continuously injected into these hypoxemiamodel animals intravenously (0.1 mg/kg/min, 10 min), and then a partialpressure value of gases (PaO₂, PaCO₂) in arterial blood was immediatelydetermined.

Method B

Male Wistar strain rats (body weight about 300 g) were anesthetized withhalothane inhalant, and then 2.0% acetic acid was intratrachealyinjected at 0.6 ml/kg to induce a respiratory insufficiency. The animalswere intraperitonealy anesthetized with urethane-α-chloralose, and acannula was inserted into the femoral artery. After the hypoxemic state(PaO₂ : 60-70 mmHg) was observed a compound in accordance with thepresent invention (test substance) was continuously injected into thesehypoxemia model animals intravenously (0.1 mg/kg/min, 10 min), and thena partial pressure value of gases (PaO₂, PaCO₂) in arterial blood wasimmediately determined.

The results are as shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Activity for Increasing PaO.sub.2 and                                         Decreasing PaCO.sub.2 by Intravenous Injection                                                  PaO.sub.2    PaCO.sub.2                                     Test              Increasing   Decreasing                                     Compound Method   Activity ΔPaO.sub.2                                                                  Activity ΔPaCO.sub.2                     ______________________________________                                        112      A        +4.6         -2.0                                           121      B        +15.9        -1.2                                           143      B        +8.1         -0.7                                           145      B        +11.2        -0.8                                           146      B        +6.6         +2.5                                           153      B        +10.0        -0.9                                           155      B        +6.6         +2.6                                           159      A        +4.8         +0.4                                           168      B        +14.4        -12.2                                          171      B        +17.4        -13.4                                          184      B        +10.4        -3.2                                           189      B        +16.0        -7.6                                           203      B        +9.5         -2.1                                           204      B        +15.0        +2.2                                           209      B        +7.6         -2.4                                           213      B        +10.3        -2.9                                           214      B        +9.8         +2.2                                           233      B        +8.6         -4.0                                           ______________________________________                                         Unit: mmHg                                                                    (indication of activity)                                                      ΔPaO.sub.2 = (PaO.sub.2 after administration  PaO.sub.2 before          administration) for test compound                                             ΔPaCO.sub.2 = (PaCO.sub.2 after administration  PaCO.sub.2 before       administration) for test compound                                        

Example 76: Effect on Partial Pressure Value of Gases in Arterial Blood(Oral Administration System)

Male Wistar strain rats (body weight about 250 g) fasted overnight wereanesthetized with halothane inhalant, and then a cannula was insertedinto the femoral artery. After the animals recovered from theanesthesia, they were again anesthetized with halothane inhalant, andthen 2.0% acetic acid was intratrachealy injected at 0.8 ml/kg to inducea hypoxemia state. After the hypoxemic state was observed over about 60min., a compound in accordance with the present invention (testsubstance) was orally administered to the animals. On 60 min. after theadministration, the partial pressure value of gases (PaO₂, PaCO₂) inarterial blood was determined.

The results are as shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Activity for Increasing PaO.sub.2 and                                         Decreasing PaCO.sub.2 by Oral Administration                                               PaO.sub.2 Increasing                                                                      PaCO.sub.2 Decreasing                                Test Compound                                                                              Activity ΔPaO.sub.2                                                                 Activity ΔPaCO.sub.2                           ______________________________________                                        121          ++          +                                                    143          +           ±                                                 145          +           ±                                                 155          ++          +                                                    171          +           ±                                                 209          +           +                                                    ______________________________________                                         (Indication of activity)                                                      ΔPaO.sub.2 = (PaO.sub.2 after administration  PaO.sub.2 before          administration) of test compound                                              ΔPaCO.sub.2 = (PaCO.sub.2 after administration  PaCO.sub.2 before       administration) of test compound                                              ΔPaO.sub.2                                                              +: +3-+6 mmHg                                                                 ++: +6-+9 mmHg                                                                ΔPaCO.sub.2                                                             ±: 0--3 mmHg                                                               +: -3--6 mmHg                                                                 ++: -6--9 mmHg                                                           

Example 77: Preparation of Tablet

A tablet containing 30 mg of the compound prepared in Example 1 wasprepared as follows:

    ______________________________________                                        Compound prepared in Ex. 1                                                                        30 mg                                                     Lactose             87 mg                                                     Starch              30 mg                                                     Magnesium stearate   3 mg                                                     ______________________________________                                    

Example 78: Preparation of Injection

A solution for injection containing 0.3 mg, based on 1 ml of thesolution, of the compound prepared in Example 1 was prepared accordingto the following formulation.

    ______________________________________                                        Compound prepared in Ex. 1                                                                            30     mg                                             Sodium chloride         900    mg                                             Distilled water for injection                                                                         100    ml                                             ______________________________________                                    

INDUSTRIAL APPLICABILITY

The compounds in the present invention, and pharmaceutical preparationsthereof, are particularly useful for the treatment of hypoxemiaassociated with respiratory diseases, and further, an effective processfor preparing of same is provided.

We claim:
 1. A fused pyrimidine derivative represented by formula (I):##STR434## wherein: R¹ represents a hydrogen atom, or an unsubstitutedor substituted alkyl, alkenyl, arylalkyl, arylalkenyl or alkylcarbonylgroup;R² and R³ independently of each other represent a hydrogen atom,or an unsubstituted or substituted alkyl, alkenyl, arylalkyl,arylalkenyl or alkylcarbonyl group; or R² and R³ are optionally takentogether with the adjacent nitrogen atom to form an unsubstitutedsaturated 5- to 7- membered ring, which may be constructed with one ortwo hetero atoms selected from the group consisting of N, O and S, withthe proviso that either R² or R³ represents a group other than ahydrogen atom; Y represents a linking group of the formula ##STR435##wherein n is an integer of from 4 to 6, ##STR436## wherein A is ahydrogen atom or alkyl group; and Z, when bonded to a carbon atom on thelinking group, represents a hydrogen atom, or carboxylic, amino orhydroxyl group, or an unsubstituted or substituted alkyl, aryl,arylalkyl, alkyloxy, alkylcarbonyloxy, alkyloxycarbonyl,arylcarbonyloxy, arylalkylcarbonyloxy, arylalkenylcarbonyloxy,alkylamino, alkenylamino, arylamino, arylalkylamino oralkylcarbonylamino group; and when bonded to an atom other than saidcarbon atom of the linking group, represents a hydrogen atom, or anunsubstituted or substituted alkyl, alkenyl, aryl, arylalkyl,arylalkenyl, alkylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl orarylcarbonyl group; or Y and Z together represent an unsubstituted orsubstituted alkyl, alkenyl or arylalkyl group; or a 5- to 7-memberheterocyclic ring which has a nitrogen atom, and further, an oxygen orsulfur atom as a hetero atom other than the nitrogen atom, being bondedvia the nitrogen atom therein to the 4-position of the pyrimidine ringof the formula (I), a 5- to 7- member unsaturated heterocyclic ringwhich has 1 to 3 nitrogen atoms being bonded via the nitrogen atomtherein to the 4-position of the pyrimidine ring of the formula (I), ora fused biheterocyclic ring, constructed with 5- or 6- membered aromaticor non-aromatic rings, which has 1 to 3 nitrogen atoms in any position,being bonded via the nitrogen atom therein to the 4-position of thepyrimidine ring of the formula (I); m is an integer of from 1 to 3; andin said substituted alkyl, alkenyl, aryl, arylalkyl, arylalkenyl,alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, arylalkenylcarbonyloxy, alkylamino, arylamino,arylalkylamino and alkylcarbonylamino groups, the substituent representsan alkyl, halogenated alkyl, alkyloxy, alkylcarbonyloxy, hydroxyl,amino, nitro or cyano group, or a halogen atom, which is bonded to achain or ring moiety in said substituted groups, or alkylene group beingtaken together with a carbon atom in the chain moiety to form a ring;and a pharmaceutically acceptable acid addition salt thereof.
 2. Apharmaceutical preparation comprising a pharmaceutical carrier and aderivative, or an acid addition salt thereof, of a fused pyrimidinederivative represented by the following formula (I): ##STR437## wherein:R¹ represents a hydrogen atom, or an unsubstituted or substituted alkyl,alkenyl, arylalkyl, arylalkenyl or alkylcarbonyl group;R² and R³,independently of each other, represent a hydrogen atom, or anunsubstituted or substituted alkyl, alkenyl, arylalkyl, arylalkenyl oralkylcarbonyl group; or R² and R³ are optionally taken together with theadjacent nitrogen atom to form an unsubstituted saturated 5- to 7-membered ring, which may be constructed with one or two hetero atomsselected from the group consisting of N, O and S, with the proviso thateither R² or R³ represents a group other than a hydrogen atom; Yrepresents a linking group of the formula ##STR438## wherein n is aninteger of from 4 to 6 ##STR439## wherein A is a hydrogen atom or alkylgroup; and Z, when bonded to a carbon atom on the linking group,represents a hydrogen atom, or carboxylic, amino or hydroxyl group, oran unsubstituted or substituted alkyl, aryl, arylalkyl, alkyloxy,alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, arylalkenylcarbonyloxy, alkylamino, alkenylamino,arylamino, arylalkylamino or alkylcarbonylamino group; and when bondedto an atom other than said carbon atom of the linking group, representsa hydrogen atom, or an unsubstituted or substituted alkyl, alkenyl,aryl, arylalkyl, arylalkenyl, alkylcarbonyl, arylalkylcarbonyl,arylalkenylcarbonyl or arylcarbonyl group; or Y and Z together representan unsubstituted or substituted alkyl, alkenyl or arylalkyl group; or a5- to 7-member heterocyclic ring which has a nitrogen atom, and further,an oxygen or sulfur atom as a hetero atom other than the nitrogen atom,being bonded via the nitrogen atom therein to the 4-position of thepyrimidine ring of the formula (I), a 5- to 7- member unsaturatedheterocyclic ring which has 1 to 3 nitrogen atoms being bonded via thenitrogen atom therein to the 4-position of the pyrimidine ring of theformula (I), or a fused biheterocyclic ring constructed with 5- or 6-membered aromatic or non-aromatic rings, which has 1 to 3 nitrogen atomsin any position, being bonded via the nitrogen atom therein to the4-position of the pyrimidine ring of the formula (I); m is an integer offrom 1 to 3; and in said substituted alkyl, alkenyl, aryl, arylalkyl,arylalkenyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl,arylalkenylcarbonyl, alkylcarbonyloxy, alkyloxycarbonyl,arylcarbonyloxy, arylalkylcarbonyloxy, arylalkenylcarbonyloxy,alkylamino, arylamino, arylalkylamino and alkylcarbonylamino groups, thesubstituent represents an alkyl, halogenated alkyl, alkyloxy,alkylcarbonyloxy, hydroxyl, amino, nitro or cyano group, or a halogenatom, which is bonded to a chain or ring moiety in said substitutedgroups, or alkylene group being taken together with a carbon atom in thechain moiety to form a ring; and a pharmaceutically acceptable acidaddition salt thereof.
 3. A method for treating hypoxemia associatedwith a respiratory disease by using a pharmaceutically effective amountof a pharmaceutical preparation comprising a derivative, or an acidaddition salt thereof, of a fused pyrimidine derivative represented bythe following formula (I): ##STR440## wherein: R¹ represents a hydrogenatom, or an unsubstituted or substituted alkyl, alkenyl, arylalkyl,arylalkenyl or alkylcarbonyl group;R² and R³, independently of eachother, represent a hydrogen atom, or an unsubstituted or substitutedalkyl, alkenyl, arylalkyl, arylalkenyl or alkylcarbonyl group; or R² andR³ are optionally taken together with the adjacent nitrogen atom to forman unsubstituted saturated 5- to 7- membered ring, which may beconstructed with one or two hetero atoms selected from the groupconsisting of N, O and S, with the proviso that either R² or R³represents a group other than a hydrogen atom; Y represents a linkinggroup of the formula ##STR441## wherein n is an integer of from 4 to 6,##STR442## wherein A is a hydrogen atom or alkyl group; and Z, whenbonded to a carbon atom on the linking group, represents a hydrogenatom, or carboxylic, amino or hydroxyl group, or an unsubstituted orsubstituted alkyl, aryl, arylalkyl, alkyloxy, alkylcarbonyloxy,alkyloxycarbonyl, arylcarbonyloxy, arylalkylcarbonyloxy,arylalkenylcarbonyloxy, alkylamino, alkenylamino, arylamino,arylalkylamino or alkylcarbonylamino group; and when bonded to an atomother than said carbon atom of the linking group, represents a hydrogenatom, or an unsubstituted or substituted alkyl, alkenyl, aryl,arylalkyl, arylalkenyl, alkylcarbonyl, arylalkylcarbonyl,arylalkenylcarbonyl or arylcarbonyl group; or Y and Z together representan unsubstituted or substituted alkyl, alkenyl or arylalkyl group; or a5- to 7-member heterocyclic ring which has a nitrogen atom, and further,an oxygen or sulfur atom as a hetero atom other than the nitrogen atom,being bonded via the nitrogen atom therein to the 4-position of thepyrimidine ring of the formula (I), a 5- to 7- member unsaturatedheterocyclic ring which has 1 to 3 nitrogen atoms being bonded via thenitrogen atom therein to the 4-position of the pyrimidine ring of theformula (I), or a fused biheterocyclic ring constructed with 5- or 6-membered aromatic or non-aromatic rings, which has 1 to 3 nitrogen atomsin any position, being bonded via the nitrogen atom therein to the4-position of the pyrimidine ring of the formula (I); m is an integer offrom 1 to 3; and in said substituted alkyl, alkenyl, aryl, arylalkyl,arylalkenyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl,arylalkenylcarbonyl, alkylcarbonyloxy, alkyloxycarbonyl,arylcarbonyloxy, arylalkylcarbonyloxy, arylalkenylcarbonyloxy,alkylamino, arylamino, arylalkylamino and alkylcarbonylamino groups, thesubstituent represents an alkyl, halogenated alkyl, alkyloxy,alkylcarbonyloxy, hydroxyl, amino, nitro or cyano group, or a halogenatom, which is bonded to a chain or ring moiety in said substitutedgroups, or alkylene group being taken together with a carbon atom in thechain moiety to form a ring; and a pharmaceutically acceptable acidaddition salt thereof.
 4. A derivative and pharmaceutically acceptableacid addition salt thereof in accordance with claim 1, wherein m is aninteger of
 2. 5. A derivative and pharmaceutically acceptable acidaddition salt thereof in accordance with claim 1, wherein R¹ is selectedfrom the group consisting of an unsubstituted or substituted alkyl,alkenyl and arylalkyl group; and R² and R³ are selected from the groupconsisting of one of them being a hydrogen atom and another being anunsubstituted or substituted alkyl or alkenyl group.
 6. A derivative andpharmaceutically acceptable acid addition salt thereof in accordancewith claim 1, wherein Y represents a linking group of the formula##STR443## wherein n is an integer of from 4 to 6, ##STR444## wherein Ais a hydrogen atom or alkyl group; and Z, when bonded to a carbon atomon the linking group, is selected from the group consisting of ahydrogen atom, a hydroxyl group, and unsubstituted or substituted alkyl,aryl, arylalkyl, alkyloxy, alkylcarbonyloxy, alkyloxycarbonyl,alkylamino and arylalkylamino groups; and when bonded to an atom otherthan said carbon atom of the linking group, is selected from the groupconsisting of a hydrogen atom, and an unsubstituted or substitutedalkyl, alkenyl, aryl, arylalkyl, arylalkenyl, alkenylamino andarylcarbonyl, or Y and Z together represent an unsubstituted orsubstituted alkenyl or arylalkyl group; or a 5- to 7- memberheterocyclic ring which has a nitrogen atom, and further an oxygen orsulfur atom as a hetero atom other than the nitrogen atom, being bondedvia the nitrogen atom therein to the 4-position of the pyrimidine ringof the formula (I), a 5- to 7- member unsubstituted heterocyclic ringwhich has 1 to 3 nitrogen atoms, being bonded via the nitrogen atomtherein to the 4-position of the pyrimidine ring, constructed with 5- or6-membered aromatic or non-aromatic rings, of the formula (I), or afused biheterocyclic ring, constructed with 5- or 6- membered aromaticor non-aromatic rings, which has 1 to 3 nitrogen atoms in any position,being bonded via the nitrogen atom therein to the 4-position of thepyrimidine ring of the formula (I).
 7. A derivative and pharmaceuticallyacceptable acid addition salt thereof in accordance with claim 4,wherein R¹ is selected from the group consisting of methyl,cyclopropylmethyl, allyl, 2-methylallyl, benzyl, 1-phenylethyl and2-phenylethyl groups; R² and R³ are selected from the group consistingof one thereof being a hydrogen atom and another being selected from thegroup consisting of methyl, allyl and 2-methylallyl groups; Y isselected from the group consisting of the linking groups represented bythe formulae ##STR445## wherein A is a hydrogen atom, or methyl or ethylgroup; and Z, when bonded to the carbon atom, is selected from the groupconsisting of a hydrogen atom, and unsubstituted or substituted aryl andalkylcarbonyloxy groups, and when bonded to an atom other than saidcarbon atom, is selected from the group consisting of a hydrogen atom,and unsubstituted or substituted alkyl, alkenyl, aryl, and arylalkylgroups; or --Y--Z is selected from the group consisting of the formulae:##STR446##
 8. A derivative and pharmaceutically acceptable acid additionsalt thereof in accordance with claim 4, wherein R¹ is selected from thegroup consisting of methyl, allyl and 2-methylallyl; R² and R³ areselected from the group consisting of one thereof being a hydrogen atomand another being selected from the group consisting of allyl and2-methylallyl; and Y is a linking group represented by the formula##STR447## and Z is a hydrogen atom; or Y is a linking group representedby the formula ##STR448## and Z is selected from the group consisting ofa hydrogen atom, and phenyl and acetyloxy groups; or Y is a linkinggroup represented by the formula ##STR449## and Z is a hydrogen atom; orY is a linking group represented by the formula ##STR450## and Z isselected from the group consisting of a hydrogen atom, and unsubstitutedor substituted alkyl and arylalkyl groups; or Y is a linking grouprepresented by the formula ##STR451## and Z is a methyl group; or Y is alinking group represented by the formula --N(A)--, wherein A is ahydrogen atom or methyl group, and Z is selected from the groupconsisting of unsubstituted or substituted alkyl, alkenyl and arylalkylgroups; or Y is a linking group represented by the formula --S-- and Zis selected from the group consisting of cyclohexyl, 1-phenylethyl and2-phenylethyl groups; or --Y--Z is selected from the group consisting ofthe formulae ##STR452##